Syntheses and antimicrobial activity of tetrasubstituted tetrahydrofuran lignan stereoisomers

Article abstract of DOI:10.1271/bbb.90107

The syntheses of all stereoisomers of tetrasubstituted tetrahydrofuran lignan were accomplished, and the antimicrobial activity was examined. The 9, 9′-diol compound bearing (7R, 7′R, 8R, 8′R) and (7R, 7′S, 8R, 8′R) stereochemistry showed the strongest antibacterial activity against Listeria denitrificans and Bacillus subtilis, respectively. It was also found that ()-virgatusin bearing (7S, 7′R, 8S, 8′S) stereochemistry had strongest antifungal activity.

Full text of DOI:10.1271/bbb.90107

Biosci. Biotechnol. Biochem., 73 (7), 1608–1617, 2009
Syntheses and Antimicrobial Activity of Tetrasubstituted Tetrahydrofuran
Lignan Stereoisomers
y
Tomofumi NAKATO,1 Satoshi YAMAUCHI,1;2; Ryosuke TAGO,1 Koichi AKIYAMA,3
Masafumi MARUYAMA,1 Takuya SUGAHARA,1;2 Taro KISHIDA,1;2 and Yojiro KOBA
1
1Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
2South Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292, Japan
3Integrated Center for Sciences, Tarumi Station, Ehime University,
3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
Received February 10, 2009; Accepted March 23, 2009; Online Publication, July 7, 2009
[doi:10.1271/bbb.90107]
The syntheses of all stereoisomers of tetrasubstituted
tetrahydrofuran lignan were accomplished, and the
antimicrobial activity was examined. The 9,90-diol
compound bearing (7R,70R,8R,80R) and (7R,70S,8R,80R)
stereochemistry showed the strongest antibacterial
activity against Listeria denitrificans and Bacillus sub-
tilis, respectively. It was also found that (ꢀ)-virgatusin
bearing (7S,70R,8S,80S) stereochemistry had strongest
antifungal activity.
Results and Discussion
Preparation of the stereoisomers of tetrasubstituted
tetrahydrofuran lignans
Stereoisomers (ꢀ)-, (þ)-1 and (ꢀ)- and (þ)-2 were
synthesized by the same procedure as that described in
the literature (Scheme 1).10)
SN1 cyclization was planned to obtain the stereo-
chemistry of 3 and 4. Starting material 17 was obtained
by Evans’s anti aldol reaction.11) The hydroxy group of
anti-Evans aldol product 17 was protected as a triethyl-
silyl ether to give 18. The treatment of 18 with LiBH4
followed by protection of the resulting primary hydroxy
group as a tert-butyldiphenylsilyl ether gave 19. Selec-
tive deprotection of the secondary hydroxy group under
acidic conditions, followed by OsO4 oxidation, NaIO4
oxidation, and pyridinium chlorochromate oxidation
gave lactone 21. After aldol condensation using lithium
diisopropylamide, the hydroxy group of the resulting
aldol mixture (erythro=threo ¼ 1=4; coupling constant
of the new benzylic proton: erythro, J ¼ 4:4 Hz; threo,
J ¼ 7:2 Hz)12) was protected as a triethylsily ether,
giving pure threo product 22. LiBH4 reduction followed
by tert-butyldiphenylsilyl protection of the primary
hydroxy group gave benzyl alcohol 23. After selective
cleavage of the triethylsilyl ether under acidic condi-
tions, resulting diol 24 was subjected to SN1 cyclization.
The reaction with a catalytic amount of 10-camphorsul-
fonic acid gave many products; however, treatment with
methanesulfonyl chloride, followed by desilylation with
n-Bu4NF gave desired (þ)-3 (41%) and undesired 25
(56%).4) Methylation of diol 3 by using NaH and CH3I
gave (þ)-4. In the differential NOE experiment irradi-
ated at 70-H (5.44 ppm, d, J ¼ 5:0 Hz) of (þ)-4, the
effects were observed at both 8-H (2.66 ppm) and 80-H
(2.71 ppm), and the signals of both 9-H2 and 90-H2 were
disappeared. The enantiomeric excess was determined
as more than 99% by employing chiral column chro-
matography. Enantiomers (ꢀ)-3 and (ꢀ)-4 were synthe-
sized from the enantiomer of 17.
Key words: lignan; tetrahydrofuran lignan; antimicro-
bial activity
The tetrahydrofuran lignan, (ꢀ)-virgatusin, is ex-
pected to have anti-virus activity.1) In our previous
study on tetrasubstituted tetrahydrofuran lignan, the
antifungal activity2) of (ꢀ)-virgatusin and antibacterial
activity3) of (7R,70S,8R,80R)-9-O,90-O-demethyl virga-
tusin have been reported (Fig. 1). Some stereoisomers
of their compounds have been synthesized, and their
antimicrobial activities have been evaluated.4) In this
study, the other stereoisomers ((ꢀ)-, (þ)-1–(ꢀ)-, (þ)-
10) (Schemes 1–3) were synthesized, and their anti-
microbial activities were examined to show the effect
of the stereochemistry of tetrasubstituted tetrahydrofur-
an lignan. The antimicrobial activities of all 16 stereo-
isomers of tetrasubstituted tetrahydrofuran lignan were
elucidated. The activity of some tetrasubstituted tetra-
hydrofuran lignans had been reported,5) however, the
effect of stereochemistry on the antimicrobial activity
has not been described. This is the first report
describing the relationship between the stereochemistry
and antimicrobial activity of tetrasubstituted tetrahy-
drofuran lignan. There are a few reports about the effect
of stereochemistry on the biological activity of many
known biologically active lignans.6–9)
Stereoisomers 1 and 2 were synthesized by the
method described in the literature (Scheme 1).10) For
the syntheses of 3–6 (Schemes 1 and 2), SN1 cycliza-
tion using methanesulfonyl chloride or a catalytic
amount of acid was employed. To obtain 7–10, stereo-
selective hydroboration to a diene was attempted
(Scheme 3).
To construct the stereochemistry of (ꢀ)-5 and (ꢀ)-6,
triethylsilyloxy benzyl alcohols 30 and 31 or dibenzyl
alcohols 32 and 33 were selected as substrates for the
SN1 cyclization reaction. To prepare these substrates,
y
To whom correspondence should be addressed. Tel: +81-89-946-9846; Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

Tetrasubstituted Tetrahydrofuran Lignan
1609
H3CO
O
H3CO
H3CO
O
O
O
O
7
7'
7
7'
O
H3CO
8
8'
9'
(7R,7'S,8R,8'R)-9-O,9'-O-demethyl virgatusin
8
8'
HO
9
OH
H3CO
OCH3
(-)-virgatusin
Fig. 1. Antimicrobial Tetrasubstituted Tetrahydrofuran Lignans.
OTIPS
H
O
OR2
OTIPS
H
Ar1
Ar2
O
O
Ar2
Ar1
Ar1
Ar2
Ar1
7
7'
R1
e
d
c
Ar1
=
H
H
8
8'
9'
H
9
OR
OR
RO
RO
PivO
OPiv
O
O
O
O
16: R = Piv
(+)-1: R = H
14
15
f
11: R1
12: R1
=
R2 = H
O
N
g
(+)-2: R = Me
Bn
O
a
O
Ar1 = 3,4-methylenedioxyphenyl
Ar2 = 3,4-dimethoxyphenyl
O
N
=
R2 = TIPS
R2 = TIPS
b
Bn
13: R1 = HOCH2
HO H
OR2
OR
H
H
O
O
Ar1
Ar1
O
Ar2
O
Ar1
R1
l
k
m
Ar1
H
H
H
TESO
OTBDPS
Ar2
OTBDPS
23: R = TES
OTBDPS
TBDPSO
O
O
21
22
17: R1
18: R1
=
=
R2 = H
O
N
n
24: R = H
Bn
O
h
O
7'
8'
7
O
O
Ar2
Ar1
Ar2
Ar1
7'
7
O
N
o
R2 = TES
+
8
8
8'
9'
i
j
Bn
19: R1 = TBDPSOCH2 R2 = TES
20: R1 = TBDPSOCH2 R2 = H
9
OR
OR
9
RO
RO
9'
25
(+)-3: R = H
p
Ar1 = 3,4-methylenedioxyphenyl
Ar2 = 3,4-dimethoxyphenyl
(+)-4: R = Me
Scheme 1. Synthesis of (þ)-1–(þ)-4.
(a) TIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 2 h (100% yield); (b) LiBH4, MeOH, THF, r.t., 4 h (52% yield); (c) (1) OsO4, NMO, aq. acetone, tert-
BuOH, r.t., 16 h; (2) NaIO4, MeOH, r.t., 1 h; (3) PCC, MS 4A, CH2Cl2, r.t., 16 h (44%, 3 steps); (d) (1) KHMDS, 3,4-dimethoxybenzaldehyde,
THF, ꢀ70 ꢁC, 30 min (81% yield); (2) LiBH4, THF, 0 ꢁC, 16 h; (3) PivCl, pyr., r.t., 1 h; (4) PCC, MS 4A, CH2Cl2, 16 h (43% yield, 3 steps);
(e) (1) n-Bu4NF, AcOH, THF, r.t., 30 min; (2) H2, 10% Pd(OH)2/C, EtOAc, r.t., 10 min (58% yield, 2 steps); (f) aq. NaOH, EtOH, r.t., 16 h
(63% yield); (g) NaH, CH3I, THF, r.t., 16 h (100% yield); (h) TESOTf, 2,6-lutidine, CH2Cl2, r.t., 30 min (100% yield); (i) (1) LiBH4, THF, r.t.,
2.5 h; (2) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t., 2 h (41% yield, 2 steps); (j) 6 M aq. HCl, THF, 0 ꢁC, 30 min (100% yield); (k) (1) OsO4, NMO,
aq. acetone, tert-BuOH, r.t., 16 h; (2) NaIO4, MeOH, r.t., 1 h; (3) PCC, MS 4A, CH2Cl2, r.t., 16 h (67% yield, 3 steps); (l) (1) LDA,
3,4-dimethoxybenzaldehyde, THF, ꢀ70 ꢁC, 1 h (erythro=threo ¼ 1=4, 98% yield); (2) TESOTf, 2,6-lutidine, CH2Cl2, r.t., 30 min (62% yield);
(m) (1) LiBH4, THF, 65 ꢁC, 3 h; (2) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t., 2 h (62% yield, 2 steps); (n) 6 M aq. HCl, THF, 0 ꢁC, 1 h (92%);
(o) (1) MsCl, Et3N, CH2Cl2, r.t., 1 h (mixture of (7R,70R) and (7S,70S), 64% yield); (2) TBAF, THF, r.t., 1 h (3: 41% yield, 25: 56% yield);
(p) NaH, CH3I, THF, r.t., 16 h (93% yield).
syn-Evans aldol product 2610) was used as a starting
material (Scheme 2). This compound 26 was converted
to primary alcohol 28 by protection as a triethylsilyl ether
and LiBH4 reduction. OsO4 oxidation, NaIO4 oxidation,
and pyridinium chlorochromate oxidation gave lactone
29. The aldol condensation of this lactone 29 with
piperonal, using potassium bis(trimethylsilyl)amide,
gave the corresponding aldol product as a 5/1 mixture
of erythro and threo (coupling constant of the new
benzylic proton: erythro, J ¼ 2:9 Hz; threo, J ¼ 6:8
Hz).12) The LiBH4 reduction of the aldol mixture,
followed by protection of the resulting primary hydroxy
group as a tert-butyldiphenylsilyl ether gave separable
benzyl alcohol derivatives 1S-30 and 1R-31. The
partially separated major erythro aldol product could
be converted to 1S-30. Selective cleavage of the
triethylsilyl group of 30 and 31 under acidic conditions
gave 32 and 33, respectively. Treatment of 30 and 31
with methanesulfonyl chloride and then tetra-n-butyl
ammonium fluoride at ꢀ10 ꢁC stereoconvergently gave
34 as a single isomer. However, the yield was very low,
and many unknown compounds were obtained. It could
be assumed that benzylic SN1 cyclization of 4S-diol 32
might give the desired stereochemistry, so attaching a 4-
benzylic hydroxy group to the 1-benzylic cation of 4S-
32 and attaching a 1-benzylic hydroxy group to the 4-

1610
T. NAKATO et al.
OTES
OH
OH
OH
OR2
OTES
H
Ar1
H
Ar2
Ar1
H
Ar2
Ar1
R1
4
d
1
e
c
1
Ar1
H
H
H
H
H
TBDPSO
OTBDPS
TBDPSO
OTBDPS
O
O
O
O
30: 1S, 31: 1R
32: 4S, 33: 4R
29
26: R1 =
27: R1 =
R2 = H
O
O
N
O
Ar1
Ar2
7'
7
Bn
O
a
32
34: R = TBDPS
(-)-5: R = H
O
f
g
h
30
31
8'
8
N
R2 = TES
R2 = TES
9
(-)-6: R = Me
OR
9'
RO
Bn
b
Ar1 = 3,4-dimethoxyphenyl
Ar2 = 3,4-methylenedioxyphenyl
28: R1 = HOCH2
Scheme 2. Synthesis of (ꢀ)-5 and (ꢀ)-6.
(a) TESOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 30 min (97% yield); (b) LiBH4, MeOH, THF, r.t., 30 min (41% yield); (c) (1) OsO4, NMO,
aq. acetone, tert-BuOH, r.t., 16 h; (2) NaIO4, MeOH, r.t., 1 h; (3) PCC, MS 4A, CH2Cl2, r.t., 16 h (71% yield, 3 steps); (d) (1) KHMDS,
piperonal, ꢀ70 ꢁC, 1 h (mixture of erythro=threo ¼ 5=1, 91% yield); (2) LiBH4, THF, 0 ꢁC, 16 h; (3) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t.,
3 h (30: 67% yield, 2 steps; 31: 15% yield, 2 steps); (e) 6 M aq. HCl, THF, r.t., 10 min (32: 73% yield; 33: 78% yield); (f) method A: CSA,
CH2Cl2, 18 h (from (1S)-32, 96% yield); method B: (1) MsCl, Et3N, benzene, 0 ꢁC, 1 h; (2) n-Bu4NF, THF, ꢀ10 ꢁC, 1 h (from 30, 19% yield,
from 31, 15% yield); (g) n-Bu4NF, THF, r.t., 2 h (86% yield); (h) NaH, CH3I, THF, r.t., 16 h (91% yield).
O
Ar1
Ar2
O
Ar1
Ar2
7
7'
O
Ar1
Ar2
OH
HO
a
b
25
8
8'
9'
O
Ar1
Ar2
OR
9
RO
35
(-)-7: R = H
c
OH
(-)-8: R = Me
HO
(-)-5
O
O
Ar1
Ar2
Ar1
Ar2
7'
7
O
Ar1
Ar2
e
d
8
8'
9'
OH
OR
9
HO
RO
36
37
(+)-9: R = H
f
(+)-10: R = Me
Ar1 = 3,4-dimethoxyphenyl, Ar2 = 3,4-methylenedioxyphenyl
Scheme 3. Synthesis of (ꢀ)-7–(þ)-10.
ꢁ
.
(a) (1) MsCl, Et3N, CH2Cl2, r.t., 30 min; (2) NaI, DBU, DMF, 80 C, 3 h (58% from 25, 52% from (ꢀ)-5, 2 steps); (b) (1) BH3 SMe2, THF,
r.t., 1 h; (2) H2O2, sat. aq. NaHCO3, r.t., 2 h (47% yield); (c) NaH, CH3I, THF, r.t., 16 h (100% yield); (d) (1) TsCl, Pyr., r.t., 1 h; (2) NaI, DBU,
ꢁ
.
DMF, 80 C, 3 h (34%, 2 steps); (e) (1) BH3 SMe2, THF, r.t., 30 min; (2) H2O2, sat. aq. NaHCO3, r.t., 2 h (49% yield); (f) NaH, CH3I, THF, r.t.,
16 h (81% yield).
benzylic cation of 4S-32 would give the desired stable
symmetrical stereochemistry of 34. The reaction of 4S-
dibenzyl alcohol 32 with a catalytic amount of 10-
camphorsulfonic acid gave 34 as a single isomer in 96%
yield, however, the reaction of 4R-dibenzyl alcohol 33
gave a mixture of many products containing the desired
compound under the same conditions. The 1H-NMR
spectrum of 34 suggested a symmetrical structure, and
NOE between two benzylic protons and methylene
protons of the 9 and 90 positions was observed. Disilyl
compound 34 was converted to (ꢀ)-5 and (ꢀ)-6. The
enantiomeric excess was determined as more than 99%
by employing chiral column chromatography. Enan-
tiomers (þ)-5 and (þ)-6 were synthesized from the
enantiomer of 26.
attempted (Scheme 3). Diene 35 was obtained from 25
or (ꢀ)-5 by conversion to a dimesylate followed by
treatment with NaI and 1,8-diazabicyclo[5.4.0]undec-7-
ene. Diol 36 was transformed to diene 37 by the same
method. Although the yields were low, desired diols
(ꢀ)-7 and (þ)-9 were obtained from dienes 35 and 37 as
single isomers, respectively. The NMR spectra of (ꢀ)-7
and (þ)-9 showed a symmetrical structure. Diols (ꢀ)-7
and (þ)-9 were respectively converted to (ꢀ)-8 and (þ)-
10, which were determined as being more than 99% ee
by using a chiral column. Enantiomers (þ)-7 and (þ)-8
were synthesized from the enantiomer of 25 or (þ)-5.
Enantiomers (ꢀ)-9 and (ꢀ)-10 were synthesized from
the enantiomer of 36. The syntheses of all 16 stereo-
isomers of tetrasubstituted tetrahydrofuran lignan were
achieved.
To prepare (ꢀ)-7, (ꢀ)-8, (þ)-9, and (þ)-10, stereo-
selective hydroboration to dienes 35 and 37 was

Tetrasubstituted Tetrahydrofuran Lignan
1611
Table 1. Antibacterial Activity of Stereoisomers (MIC, mM)
O
Ar1
Ar2
O
O
O
Ar1
Ar2
O
Ar2
Ar1
Ar1
Ar2
7
7
Ar1
Ar2
7'
8'
7'
8'
8
8
OH
OH
OH
HO
OH
OH
HO
HO
HO
HO
(+)-1
(-)-7
(+)-7
(+)-9
(-)-9
B. subtilis
S. aureus
L. denitrificans
>50
>50
25
>50
>50
>50
>50
6.25
>50
>50
50.0
>50
>50
25
50.0
Ar1 ¼ 3,4-dimethoxyphenyl, Ar2 ¼ 3,4-methylenedioxyphenyl
Table 2. Growth Rate (% ꢃ ꢂ, n ¼ 3) of Colletotrichum lagenarium at 0.25 mM of the Stereoisomers
O
7
Ar1
Ar2
O
7'
7
O
7'
8'
Ar1
Ar2
Ar1
Ar2
7
7'
8
8'
8
8
8'
OCH3
OCH3
H3CO
OCH3
H3CO
H3CO
(+)-6
(+)-10
(-)-10
86.6 3.71
92.6 5.12
83.4 4.15
Ar1 ¼ 3,4-dimethoxyphenyl, Ar2 ¼ 3,4-methylenedioxyphenyl
Growth (%), (colony diameter of sample/colony diameter of control) ꢄ 100.
Antimicrobial activity
Material and Methods
In the antibacterial activity test, the (7R,70R,8R,80R)
form ((þ)-7) showed the strongest activity (MIC of
6.25 mM) against Listeria denitrificans (Table 1). This
activity was stronger than that of the (7S,70R,8R,80S)
stereoisomer (MIC of 12.5 mM).4) The other stereo-
isomers showed weaker activity. The (7’R,8R) stereo-
chemistry was found in those compounds having the
highest antibacterial activity against Listeria denitrifi-
cans, and the (7R,70R,8R,80R) form ((þ)-7)) was the
best stereochemistry. Against Bacillus subtilis, the
(7R,70S,8R,80R) form (Fig. 1) was the best stereochem-
istry (MIC of 12.5 mM),3) because the other stereoisomers
did not show activity against Bacillus subtilis in this
and previous studies.3,4) The 8R form is common
stereochemistry for high antibacterial activity against
Listeria denitrificans and Bacillus subtilis. In the anti-
fungal activity test against Colletotrichum lagenarium
(Table 2), (þ)-6, (þ)-10, and (ꢀ)-10 showed weaker
activity at 0.25 mM than that of natural (ꢀ)-virgatusin
bearing (7S,70R,8S,80S) stereochemistry (50% growth
inhibition).2) Since the compounds having other stereo-
chemistry did not show stronger activity,2,4) the natural
(7S,70R,8S,80S) stereochemistry was best for antifungal
activity. The weaker activity of the (7R,70S,8R,80R),
(7S,70R,8R,80S), (7R,70S,8R,80S), (7S,70R,8S,80R), and
(7R,70R,8S,80S) stereoisomers was observed in this and
previous studies. In the case of epimers with natural
stereochemistry, only 70 the epimer did not show any
activity, white the activity of the other epimers was
weak. With stereochemistries bearing the (7S,70R) form,
only (8R,80R) stereochemistry did not show any activity.
The effect of the stereochemistry of tetrasubstituted
tetrahydrofuran lignan on antimicrobial activity was
demonstrated for the first time.
Melting point (mp) data are uncorrected. NMR data were measured
by a JNM-EX400 spectrometer, using TMS as a standard (0 ppm), MS
data were measured with a JMS-MS700V spectrometer, and optical
rotation values were evaluated with a Horiba SEPA-200 instrument.
Elemental analysis was carried out with Yanako MT-5 CHN coder.
The silica gel used was Wakogel C-300 (Wako, 200–300 mesh).
(S)-4-Benzyl-3-{(S)-2-[(S)-(3,4-methylenedioxyphenyl)(triisopropyl-
silyloxy)methyl]-4-pentenoyl}-2-oxazolidinone (12). To an ice-cooled
solution of 11 (17.3 g, 0.042 mol) and 2,6-lutidine (8.43 ml, 0.072 mol)
in CH2Cl2 (200 ml) was added TIPSOTf (14.4 ml, 0.054 mol). The
resulting reaction solution was stirred at room temperature for 2 h
before addition of sat. aq. NaHCO3 solution. The organic solution was
separated, washed with sat. aq. CuSO4 solution and sat. aq. NaHCO3
solution, and dried (Na2SO4). Concentration followed by silica gel
column chromatography (EtOAc/hexane ¼ 1=4) gave 12 (23.8 g, 0.042
20
mol, 100%) as a colorless oil, ½ꢀꢂ
þ45 (c 1.1, CHCl3). NMR ꢁH
D
(CDCl3): 0.96–1.06 (19H, m), 1.13–1.16 (2H, m), 2.60 (1H, dd,
J ¼ 13:2, 9.8 Hz), 2.65 (1H, m), 2.77 (1H, m), 3.14 (1H, dd, J ¼ 13:2,
2.9 Hz), 3.65 (1H, dd, J ¼ 8:3, 8.3 Hz), 3.95 (1H, dd, J ¼ 8:3, 2.0 Hz),
4.25 (1H, m), 4.43 (1H, m), 4.87 (1H, d, J ¼ 7:8 Hz), 5.02 (1H, d,
J ¼ 9:8 Hz), 5.11 (1H, d, J ¼ 17:1 Hz), 5.81–5.93 (1H, m), 5.90 (1H, d,
J ¼ 6:8 Hz), 5.91 (1H, d, J ¼ 6:8 Hz), 6.69 (1H, d, J ¼ 7:8 Hz), 6.78
(1H, dd, J ¼ 7:8, 2.0 Hz), 6.90 (1H, d, J ¼ 2:0 Hz), 7.16 (2H, d,
J ¼ 6:4 Hz), 7.22–7.31 (3H, m). NMR ꢁC (CDCl3): 12.4, 12.5, 17.9,
18.1, 34.0, 37.9, 51.9, 55.7, 65.6, 76.9, 100.9, 107.4, 107.6, 116.8,
120.4, 127.2, 128.8, 129.4, 135.4, 136.8, 146.9, 147.2, 152.7, 173.6.
Found: C, 68.05; H, 7.77; N 2.49. Calcd. for C32H43O6NSi: C, 67.93;
20
H, 7.66; N, 2.47%. (R)-{(R)-[(R)]}-(12), ½ꢀꢂ
ꢀ44 (c 0.8, CHCl3).
D
(R)-2-[(S)-(3,4-Methylenedioxyphenyl)(triisopropylsilyloxy)methyl]-
4-penten-1-ol (13). To an ice-cooled solution of LiBH4 (1.00 g,
0.046 mol) and MeOH (1.86 ml) in THF (50 ml) was added a solution
of 12 (27.3 g, 0.048 mol) in THF (100 ml). After the reaction solution
was stirred at room temperature for 4 h, sat. aq. NH4Cl solution was
added. The mixture was concentrated, and then the residue was
dissolved in H2O and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration followed by

1612
T. NAKATO et al.
silica gel column chromatography (EtOAc/hexane ¼ 1=4) gave 13
12.5, 18.0, 18.1, 27.0, 27.1, 38.5, 38.7, 43.6, 46.7, 55.9, 56.1, 61.4,
62.9, 73.7, 101.0, 107.1, 107.7, 109.9, 110.8, 120.4, 123.3, 129.6,
136.1, 147.2, 147.7, 149.2, 153.5, 177.8, 178.0, 198.2. Found: C,
20
(10.0 g, 0.025 mol, 52%) as a colorless oil, ½ꢀꢂ
ꢀ22 (c 0.6, CHCl3).
D
NMR ꢁH (CDCl3): 0.96–1.07 (19H, m), 1.13–1.16 (2H, m), 1.75 (1H,
m), 1.94 (1H, m), 2.23 (1H, m), 3.19 (1H, dd, J ¼ 5:4, 2.0 Hz), 3.47
(1H, m), 3.61 (1H, ddd, J ¼ 8:8, 8.8, 2.0 Hz), 4.93 (1H, d, J ¼ 4:4 Hz),
5.02–5.07 (2H, m), 5.79 (1H, m), 5.96 (2H, s), 6.77 (2H, s), 6.89 (1H,
s). NMR ꢁC (CDCl3): 12.1, 17.8, 17.9, 18.0, 32.6, 46.8, 63.2, 77.8,
100.9, 107.6, 107.7, 120.5, 134.7, 146.8, 147.4. Found: C, 67.24; H,
65.79; H, 8.24. Calcd. for C40H60O10Si: C, 65.90; H 8.30%. (2S,3S)-
20
[(R)]-(15), ½ꢀꢂ
þ5 (c 0.4, CHCl3).
D
(7S,70R,8R,80R)-30,40-Dimethoxy-3,4-methylenedioxy-7,70-epoxy-
lignane-9,90-diyl dipivaloate (16). To an ice-cooled solution of 15
(2.65 g, 3.64 mmol) in THF (15 ml) were added AcOH (0.25 ml) and
n-Bu4NF (4.00 ml, 1 M in THF, 4.00 mmol). After the reaction solution
was stirred at room temperature for 30 min, sat. aq. NaHCO3 solution
was added. The organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration gave a crude hemiacetal. A reaction
mixture of this crude hemiacetal and 10% Pd(OH)2/C (0.7 g) in EtOAc
(15 ml) was stirred at ambient temperature for 10 min under H2 gas
before filtration. The resulting filtrate was concentrated, and then the
residue was applied to silica gel column chromatography (EtOAc=
9.20. Calcd. for C22H36O4Si: C, 67.30; H, 9.24%. (S)-2-[(R)]-(13),
20
½ꢀꢂ
þ21 (c 0.4, CHCl3).
D
(R)-3-[(S)-(3,4-Methylenedioxyphenyl)(triisopropylsilyloxy)methyl]-
4-butanolide (14). A reaction solution of 13 (10.0 g, 0.025 mol), NMO
(3.76 g, 0.032 mol), and OsO4 (3.5 ml, 2% in H2O) in acetone (250 ml),
tert-BuOH (50 ml), and H2O (50 ml) was stirred under N2 gas at room
temperature for 16 h before addition of sat. aq. Na2S2O3 solution. After
the mixture was concentrated, the residue was dissolved in H2O and
EtOAc. The organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration gave a crude glycol. A reaction mixture
of this crude glycol and NaIO4 (7.52 g, 0.035 mol) in MeOH (150 ml)
was stirred at room temperature for 1 h before concentration. The
residue was dissolved in CH2Cl2 and H2O. The organic solution was
separated and dried (Na2SO4). Concentration gave crude hemiacetal. A
reaction mixture of this crude hemiacetal, PCC (6.50 g, 0.030 mol), and
MS 4A (0.5 g) in CH2Cl2 (200 ml) was stirred at room temperature for
16 h before addition of ether. After the mixture was filtered, the filtrate
was concentrated. The residue was applied to silica gel column
hexane ¼ 1=3) to give 16 (1.18 g, 2.12. mmol, 58%, 2 steps) as a
20
colorless oil, ½ꢀꢂ
þ13 (c 0.9, CHCl3). NMR ꢁH (CDCl3): 1.08 (9H,
D
s), 1.20 (9H, s), 2.33 (1H, m), 2.73 (1H, m), 3.76 (1H, dd, J ¼ 11:2,
8.7 Hz), 3.85 (1H, dd, J ¼ 11:2, 6.2 Hz), 3.87 (3H, s), 3.90 (3H, s),
4.21 (1H, dd, J ¼ 11:5, 5.5 Hz), 4.28 (1H, dd, J ¼ 11:5, 5.5 Hz), 4.67
(1H, d, J ¼ 8:5 Hz), 5.13 (1H, d, J ¼ 7:5 Hz), 5.98 (2H, s), 6.81–6.86
(2H, m), 6.91–6.96 (3H, m), 7.01 (1H, d, J ¼ 1:5 Hz). NMR ꢁC
(CDCl3): 27.0, 27.1, 38.6, 38.9, 45.3, 50.8, 55.9, 63.8, 64.9, 81.1, 82.8,
101.1, 106.8, 108.2, 109.5, 111.1, 118.6, 120.3, 130.2, 133.9, 147.5,
148.0, 148.5, 148.9, 178.2, 178.3. Found: C, 67.02; H, 7.33. Calcd.
20
for C31H40O9: C, 66.89; H, 7.24%. (7R,70S,8S,80S)-(16), ½ꢀꢂ
ꢀ13
chromatography (EtOAc/hexane ¼ 1=4) to give 14 (4.38 g, 0.011 mol,
D
20
(c 0.4, CHCl3).
44%, 3 steps) as a colorless oil, ½ꢀꢂ
ꢀ63 (c 0.5, CHCl3). NMR ꢁH
D
(CDCl3): 0.95–1.05 (21H, m), 2.54 (1H, dd, J ¼ 17:6, 9.0 Hz), 2.62
(1H, dd, J ¼ 17:6, 7.8 Hz), 2.84 (1H, m), 4.09 (1H, dd, J ¼ 9:3,
6.8 Hz), 4.15 (1H, dd, J ¼ 9:3, 7.8 Hz), 4.68 (1H, d, J ¼ 6:4 Hz), 5.97
(2H, s), 6.71 (1H, d, J ¼ 8:1 Hz), 6.75 (1H, d, J ¼ 8:1 Hz), 6.80 (1H,
s). NMR ꢁC (CDCl3): 12.5, 18.0, 18.1, 31.0, 44.5, 69.5, 75.5, 101.1,
106.6, 108.0, 119.8, 135.9, 147.4, 147.9, 176.8. Found: C, 64.55; H,
(7S,70R,8R,80R)-30,40-Dimethoxy-3,4-methylenedioxy-7,70-epoxy-
lignane-9,90-diol ((þ)-1). A reaction solution of 16 (1.14 g, 2.05 mmol)
in EtOH (20 ml) and 1 M aq. NaOH solution (10 ml) was stirred at room
temperature for 16 h before additions of CHCl3 and H2O. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography
8.38. Calcd. for C21H32O5Si: C, 64.25; H, 8.22%. (S)-3-[(R)]-(14),
20
½ꢀꢂ
þ63 (c 0.3, CHCl3).
(EtOAc/hexane ¼ 1=6) gave (þ)-1 (0.50 g, 1.29 mmol, 63%) as a
D
20
colorless oil, ½ꢀꢂ
þ30 (c 0.5, CHCl3). NMR ꢁH (CDCl3): 2.17 (1H,
D
m), 2.54 (1H, m), 3.07 (1H, dd, J ¼ 10:6, 10.6 Hz), 3.29 (1H, dd,
J ¼ 10:6, 4.5 Hz), 3.53 (1H, dd, J ¼ 9:5, 9.5 Hz), 3.69 (1H, dd,
J ¼ 9:5, 3.7 Hz), 3.865 (3H, s), 3.869 (3H, s), 4.44 (1H, d, J ¼ 9:4 Hz),
5.09 (1H, d, J ¼ 8:5 Hz), 5.97 (2H, s), 6.80 (1H, d, J ¼ 7:9 Hz), 6.82
(1H, d, J ¼ 7:8 Hz), 6.85–6.91 (3H, m), 7.01 (1H, s). NMR ꢁC
(CDCl3): 50.8, 55.2, 55.8, 62.7, 63.6, 81.2, 82.5, 101.1, 106.9, 108.1,
109.6, 110.9, 118.7, 120.4, 131.3, 133.9, 147.5, 147.9, 148.4, 148.7.
EIMS m=z: 388 (Mþ, 100), 191 (64), 174 (65). HRMS (EI) m=z (Mþ):
(2R,3R)-2-(3,4-Dimethoxybenzoyl)-3-[(S)-(methylenedioxyphenyl)-
(triisopropylsilyloxy)methyl]tetramethylene dipivaloate (15). To
a
solution of KHMDS (24 ml, 0.5 M in toluene, 12.0 mmol) in THF
(80 ml) was added a solution of 14 (4.06 g, 10.3 mmol) in THF (20 ml)
at ꢀ70 ꢁC, and then a solution of 3,4-dimethoxybenzaldehyde (1.66 g,
0.010 mol) in THF (10 ml) was added. After the resulting solution was
stirred at ꢀ70 ꢁC for 30 min, sat. aq. NH4Cl solution was added. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
raphy (EtOAc/hexane ¼ 1=3) gave an aldol product (4.69 g, 8.39
mmol, 81%) as a mixture of erythro=threo ¼ 9=1. To a solution of
LiBH4 (1.50 g, 68.9 mmol) in THF (10 ml) was added a solution of
the aldol mixture (4.69 g, 8.39 mmol) in THF (20 ml) at ꢀ10 ꢁC. The
resulting solution was stirred at 0 ꢁC for 16 h before addition of sat. aq.
NH4Cl solution. After concentration, the residue was dissolved in H2O
and EtOAc. The organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration gave a crude triol. To an ice-cooled
solution of this crude triol in pyridine (10 ml) was added PivCl
(2.07 ml, 16.8 mmol). The resulting reaction mixture was stirred at
room temperature for 1 h before additions of EtOAc and H2O. The
organic solution was separated, washed with 6 M aq. HCl solution, sat.
aq. NaHCO3 solution, and brine, and dried (Na2SO4). Concentration
gave a crude dipivaloate. A reaction mixture of this crude dipivaloate,
PCC (1.07 g, 4.96 mmol), and MS 4A (0.2 g) in CH2Cl2 (80 ml) was
stirred at room temperature for 16 h, and then ether was added. After
filtration, the filtrate was concentrated. The resulting residue was
calcd. for C21H24O7, 388.1522; found, 388.1522. (7R,70S,8S,80S)-
20
((ꢀ)-1), ½ꢀꢂ
ꢀ30 (c 0.6, CHCl3).
D
(7S,70R,8R,80R)-30,40,9,90-Tetramethoxy-3,4-methylenedioxy-7,70-
epoxylignane ((þ)-2). To an ice-cooled suspension of NaH (0.12 g,
60% oil suspension, 3.00 mmol) in THF (5 ml) was added a solution of
(þ)-1 (0.50 g, 1.29 mmol) in THF (10 ml). After the resulting mixture
was stirred at room temperature for 30 min, CH3I (0.40 ml, 6.43 mmol)
was added. The reaction solution was stirred at room temperature for
16 h before additions of sat. aq. NH4Cl solution and EtOAc. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
raphy (EtOAc/hexane ¼ 1=1) gave (þ)-2 (0.54 g, 1.29 mmol, 100%)
20
as a colorless oil, ½ꢀꢂ
þ20 (c 0.8, CHCl3). NMR ꢁH (CDCl3): 2.30
D
(1H, m), 2.62 (1H, m), 2.94 (1H, dd, J ¼ 9:2, 5.7 Hz), 3.05 (1H, dd,
J ¼ 9:2, 9.2 Hz), 3.08 (3H, s), 3.37 (3H, s), 3.50 (1H, dd, J ¼ 9:4,
4.9 Hz), 3.54 (1H, dd, J ¼ 9:4, 5.3 Hz), 3.89 (3H, s), 3.90 (3H, s), 4.71
(1H, d, J ¼ 8:1 Hz), 5.09 (1H, d, J ¼ 7:3 Hz), 5.97 (2H, s), 6.81 (1H, d,
J ¼ 8:1 Hz), 6.85 (1H, d, J ¼ 8:1 Hz), 6.94–6.96 (3H, m), 7.05 (1H, d,
J ¼ 1:6 Hz). NMR ꢁC (CDCl3): 46.5, 51.1, 55.8, 55.9, 58.6, 59.0, 72.9,
81.5, 82.5, 100.9, 107.0, 106.9, 108.0, 109.7, 110.7, 118.5, 120.0,
131.3, 135.6, 147.0, 147.7, 148.5. EIMS m=z: 416 (Mþ, 99), 208 (58),
173 (100). HRMS (EI) m=z (Mþ): calcd. for C23H28O7, 416.1835;
found, 416.1834. >99% ee (HPLC, DAICEL OD-H chiral column,
applied to silica gel column chromatography (5% EtOAc in toluene) to
20
give 15 (2.65 g, 3.64 mmol, 43%, 3 steps) as a colorless oil, ½ꢀꢂ
ꢀ4
D
(c 1.0, CHCl3). NMR ꢁH (CDCl3): 0.99–1.15 (21H, m), 1.04 (9H, s),
1.21 (9H, s), 2.57 (1H, m), 3.84 (1H, dd, J ¼ 9:8, 3.9 Hz), 3.93 (3H, s),
3.98 (3H, s), 4.11 (1H, dd, J ¼ 9:8, 3.9 Hz), 4.28 (1H, m), 4.42 (1H,
dd, J ¼ 9:8, 3.9 Hz), 4.49 (1H, dd, J ¼ 9:8, 9.8 Hz), 4.89 (1H, d,
J ¼ 7:0 Hz), 5.92 (1H, d, J ¼ 12:5 Hz), 5.93 (1H, d, J ¼ 12:5 Hz), 6.59
(1H, d, J ¼ 7:9 Hz), 6.66 (1H, d, J ¼ 7:9 Hz), 6.74 (1H, s), 6.88 (1H, d,
J ¼ 8:3 Hz), 7.54 (1H, s), 7.61 (1H, d, J ¼ 8:3 Hz). NMR ꢁC (CDCl3):
detected at 280 nm, 1 ml minꢀ1, 10% iso-PrOH in hexane, tR 37 min).
20
(7R,70S,8S,80S)-((ꢀ)-2), ½ꢀꢂ
ꢀ21 (c 0.4, CHCl3), >99% ee, tR
D
15 min.

Tetrasubstituted Tetrahydrofuran Lignan
(S)-4-Benzyl-3-{(R)-2-[(S)-(hydroxy)(3,4-methylenedioxyphenyl)-
Calcd. for C35H48O4Si2: C, 71.36; H, 8.22%. (4R,5R)-(19), ½ꢀꢂ
1613
20
¼
D
methyl]-4-pentenoyl}-2-oxazolidinone (17). A reaction mixture of (S)-
4-benzyl-3-(4-pentenoyl)-2-oxazolidinone (22.0 g, 84.8 mmol), pipero-
nal (12.8 g, 85.3 mmol), Et3N (23.9 ml, 0.17 mol), TMSCl (16.2 ml,
0.13 mol), and MgCl2 (0.85 g, 8.92 mmol) in EtOAc (200 ml) was
stirred at room temperature for 16 h before filtration with silica gel and
ether. After the filtrate was concentrated, the residue was dissolved in
MeOH. To the resulting solution was added CF3CO2H (5 ml) at 0 ꢁC,
and then the reaction solution was stirred at 0 ꢁC for 30 min before
addition of Et3N. After concentration of the resulting mixture, the
residue was applied to silica gel column chromatography (EtOAc=
þ36 (c 1.3, CHCl3).
(1S,2S)-2-(tert-Butyldiphenylsilyloxy)methyl-1-(3,4-methylenedioxy-
phenyl)-4-penten-1-ol (20). To an ice-cooled solution of 19 (4.77 g,
8.10 mmol) in THF (5 ml) was added 6 M aq. HCl solution (5 ml). After
the resulting reaction mixture was stirred at 0 ꢁC for 30 min, EtOAc
and H2O were added. The organic solution was separated, washed with
sat. aq. NaHCO3 solution and brine, and dried (Na2SO4). Concen-
tration followed by silica gel column chromatography (EtOAc=
hexane ¼ 1=9) gave 20 (3.83 g, 8.07 mmol, 100%) as a colorless oil,
20
hexane ¼ 1=3), giving 17 (25.0 g, 61.1 mmol, 72%) as a colorless oil,
½ꢀꢂ
þ24 (c 1.2, CHCl3). NMR ꢁH (CDCl3): 1.09 (9H, s), 1.84 (1H,
D
20
½ꢀꢂ
þ8 (c 2.2, CHCl3). NMR ꢁH (CDCl3): 2.16 (1H, m), 2.40 (1H,
D
m), 2.00 (1H, m), 2.12 (1H, m), 3.66 (1H, dd, J ¼ 10:5, 5.8 Hz), 3.86
(1H, dd, J ¼ 10:5, 3.2 Hz), 4.01 (1H, d, J ¼ 4:5 Hz), 4.71 (1H, dd,
J ¼ 6:6, 4.5 Hz), 4.88 (1H, d, J ¼ 10:1 Hz), 4.90 (1H, d, J ¼ 17:2 Hz),
5.57 (1H, m), 5.94 (2H, s), 6.75 (1H, d, J ¼ 7:9 Hz), 6.79 (1H, dd,
J ¼ 7:9, 1.6 Hz), 6.88 (1H, d, J ¼ 1:6 Hz), 7.35–7.46 (6H, m), 7.63–
7.68 (4H, m). NMR ꢁC (CDCl3): 19.1, 26.9, 32.7, 46.4, 65.1, 77.1,
100.9, 106.8, 107.8, 116.6, 119.8, 127.8, 129.9, 132.58, 132.62,
m), 2.67 (1H, dd, J ¼ 13:6, 9.3 Hz), 3.15 (1H, d, J ¼ 7:3 Hz), 3.20
(1H, dd, J ¼ 13:6, 3.4 Hz), 4.10–4.13 (2H, m), 4.48 (1H, m), 4.66 (1H,
m), 4.78 (1H, dd, J ¼ 7:5, 7.3 Hz), 4.98 (1H, d, J ¼ 10:3 Hz), 5.03
(1H, d, J ¼ 7:0 Hz), 5.72 (1H, m), 5.92 (1H, d, J ¼ 9:2 Hz), 5.93 (1H,
d, J ¼ 9:2 Hz), 6.78 (1H, d, J ¼ 8:0 Hz), 6.87 (1H, dd, J ¼ 8:0,
1.5 Hz), 6.97 (1H, d, J ¼ 1:5 Hz), 7.15 (2H, d, J ¼ 6:8 Hz), 7.23–7.33
(3H, m). NMR ꢁC (CDCl3): 34.2, 37.5, 49.1, 55.4, 65.8, 75.8, 101.1,
106.9, 108.1, 117.4, 120.1, 127.2, 128.9, 129.4, 134.4, 135.2, 136.1,
147.3, 148.0, 153.5, 175.3. EIMS m=z: 409 (Mþ, 8), 259 (100), 151
135.60, 135.64, 136.1, 137.6, 146.7, 147.7. Found: C, 73.09; H, 7.47.
20
Calcd. for C29H34O4Si: C, 73.37; H, 7.22%. (1R,2R)-20, ½ꢀꢂ
(c 1.1, CHCl3).
ꢀ23
D
(62). HRMS (EI) m=z (Mþ): calcd. for C23H23O6N, 409.1525; found,
20
409.1525. (R)-{(S)-[(R)]}-17, ½ꢀꢂ
ꢀ8 (c 2.3, CHCl3).
D
(3S,4S)-3-(tert-Butyldiphenylsilyloxy)methyl-4-(3,4-methylenedioxy-
phenyl)-4-butanolide (21). reaction solution of 20 (3.40 g,
A
(S)-4-Benzyl-3-{(R)-2-[(S)-(3,4-methylenedioxyphenyl)(triethylsily-
loxy)methyl]-4-pentenoyl}-2-oxazolidinone (18). To an ice-cooled solu-
tion of 17 (2.30 g, 5.62 mmol) and 2,6-lutidine (1.33 ml, 11.4 mmol)
in CH2Cl2 (50 ml) was added TESOTf (1.91 ml, 8.45 mmol). The
resulting reaction solution was stirred at room temperature for 30 min
before addition of sat. aq. NaHCO3 solution. The organic solution was
separated, washed with sat. aq. CuSO4 solution, sat. aq. NaHCO3, and
brine, and dried (Na2SO4). Concentration followed by silica gel
7.16 mmol), NMO (0.86 g, 7.34 mmol), and OsO4 (1.00 ml, 2% aq.
solution) in acetone (64 ml), tert-BuOH (16 ml), and H2O (16 ml) was
stirred at room temperature for 16 h before addition of sat. aq. Na2S2O3
solution. After the mixture was concentrated, the residue was dissolved
in H2O and EtOAc. The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration gave a crude glycol. A
reaction mixture of this glycol and NaIO4 (2.04 g, 9.54 mmol) in
MeOH (50 ml) was stirred at room temperature for 1 h before
concentration. The resulting residue was dissolved in H2O and
CH2Cl2. The organic solution was separated and dried (Na2SO4).
Concentration gave a crude hemiacetal. A reaction mixture of this
hemiacetal, PCC (1.89 g, 8.77 mmol), and MS 4A (0.3 g) in CH2Cl2
(100 ml) was stirred at room temperature for 16 h before addition of
ether. After filtration, the filtrate was concentrated. The residue was
applied to silica gel column chromatography to give 21 (2.29 g,
column chromatography (EtOAc/hexane ¼ 1=3) gave 18 (2.94 g,
20
5.62 mmol, 100%) as a colorless oil, ½ꢀꢂ
ꢀ30 (c 1.1, CHCl3).
D
NMR ꢁH (CDCl3): 0.34–0.47 (6H, m), 0.83 (9H, t, J ¼ 8:0 Hz), 1.91
(1H, m), 2.15 (1H, m), 2.69 (1H, dd, J ¼ 13:2, 3.2 Hz), 3.46 (1H, dd,
J ¼ 13:2, 3.2 Hz), 4.07–4.14 (2H, m), 4.50 (1H, m), 4.67 (1H, m), 4.84
(1H, d, J ¼ 9:4 Hz), 4.89 (1H, d, J ¼ 10:7 Hz), 4.93 (1H, d, J ¼
17:5 Hz), 5.63 (1H, m), 5.97 (1H, d, J ¼ 4:8 Hz), 5.98 (1H, d, J ¼
4:8 Hz), 6.75 (1H, d, J ¼ 8:0 Hz), 6.82 (1H, dd, J ¼ 8:0, 1.6 Hz), 6.98
(1H, d, J ¼ 1:6 Hz), 7.24–7.30 (3H, m), 7.34–7.37 (2H, m). NMR ꢁC
(CDCl3): 4.7, 6.7, 34.1, 38.1, 50.9, 55.6, 65.7, 77.1, 101.0, 107.66,
107.70, 116.9, 121.1, 127.2, 128.9, 129.4, 134.7, 135.8, 136.4, 147.3,
147.7, 153.2, 174.7. Found: C, 66.19; H, 7.20; N, 2.62. Calcd. for
4.82 mmol, 67%, 3 steps) as colorless crystals, mp 116–117 ꢁC
20
(EtOAc), ½ꢀꢂ
þ20 (c 0.6, CHCl3). NMR ꢁH (CDCl3): 1.01 (9H,
D
s), 2.60 (1H, dd, J ¼ 17:2, 4.6 Hz), 2.72 (1H, dd, J ¼ 17:2, 8.3 Hz),
2.80 (1H, m), 3.29 (1H, dd, J ¼ 10:7, 5.2 Hz), 3.39 (1H, dd, J ¼ 10:7,
5.2 Hz), 5.57 (1H, d, J ¼ 6:8 Hz), 5.96 (2H, s), 6.70 (1H, d, J ¼ 7:9,
1.2 Hz), 6.75 (1H, d, J ¼ 7:9 Hz), 6.78 (1H, d, J ¼ 1:2 Hz), 7.30–7.36
(4H, m), 7.38–7.43 (4H, m), 7.51–7.53 (2H, m). NMR ꢁC (CDCl3):
19.0, 26.7, 32.3, 42.1, 62.1, 82.6, 101.2, 106.3, 106.4, 108.2, 119.0,
127.7, 129.5, 129.8, 132.7, 135.5, 147.3, 147.8, 176.2. Found: C,
C
29H37O6NSi: C, 66.49; H, 7.13; N, 2.68%. (R)-{(S)-[(R)]}-(18),
20
½ꢀꢂ
þ31 (c 0.6, CHCl3).
D
(4S,5S)-4-(tert-Butyldiphenylsilyloxy)methyl-5-(3,4-methylenedioxy-
70.85; H, 6.33. Calcd. for C28H30O5Si: C, 70.84; H, 6.37%. (3R,4R)-
20
phenyl)-5-(triethylsilyloxy)-1-pentene (19). To an ice-cooled solution
of LiBH4 (1.62 g, 74.4 mmol) and MeOH (1.54 ml) in THF (50 ml) was
added a solution of 18 (10.4 g, 19.9 mmol) in THF (50 ml). The
resulting reaction solution was stirred at room temperature for 2.5 h
before addition of sat. aq. NH4Cl solution. The mixture was
concentrated, and then the residue was dissolved in EtOAc and H2O.
The organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration gave crude alcohol. A reaction mixture of
this crude alcohol, Et3N (2.86 ml, 20.5 mmol), DMAP (50 mg,
0.41 mmol), and TBDPSCl (4.20 ml, 16.2 mmol) in CH2Cl2 (50 ml)
was stirred at room temperature for 2 h before addition of H2O and
CH2Cl2. The organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel column chro-
(21), ½ꢀꢂ
ꢀ20 (c 1.0, CHCl3).
D
(2S,3S,4S)-3-(tert-Butyldiphenylsilyloxy)methyl-2-[(R)-(3,4-dimeth-
oxyphenyl)(triethylsilyloxy)methyl]-4-(3,4-methylenedioxyphenyl)-4-
butanolide (22). To a solution of LDA (5.80 mmol) in THF (10 ml) was
added a solution of 21 (2.29 g, 4.82 mmol) in THF (10 ml) at ꢀ70 ꢁC,
and then a solution of 3,4-dimethoxybenzaldehyde (0.88 g, 5.30 mmol)
in THF (5 ml) was added. The reaction solution was stirred at ꢀ70 ꢁC
for 1 h before additions of sat. aq. NH4Cl solution and EtOAc. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
raphy (EtOAc/hexane ¼ 1=3) gave an aldol product (3.04 g, 4.71
mmol, 98%) as a mixture of erythro=threo ¼ 1=4. To an ice-cooled
solution of this aldol product (3.04 g, 4.71 mmol) and 2,6-lutidine
(1.10 ml, 9.44 mmol) in CH2Cl2 (20 ml) was added TESOTf (1.21 ml,
5.35 mmol). The resulting solution was stirred at room temperature for
30 min before addition of sat. aq. NaHCO3 solution. The organic
solution was separated, washed with sat. aq. CuSO4 and sat. aq.
NaHCO3 solution, and dried (Na2SO4). Concentration followed by
matography (5%EtOAc in hexane) gave 19 (4.77 g, 8.10 mmol, 41%,
20
2 steps) as a colorless oil, ½ꢀꢂ
ꢀ35 (c 1.3, CHCl3). NMR ꢁH
D
(CDCl3): 0.46 (6H, q, J ¼ 7:9 Hz), 0.84 (9H, t, J ¼ 7:9 Hz), 1.08 (9H,
s), 1.65 (1H, m), 1.94 (1H, m), 2.21 (1H, m), 3.51 (1H, dd, J ¼ 10:4,
7.1 Hz), 3.70 (1H, dd, J ¼ 10:4, 5.8 Hz), 4.82 (1H, d, J ¼ 17:1 Hz),
4.83 (1H, d, J ¼ 10:3 Hz), 4.89 (1H, d, J ¼ 5:6 Hz), 5.57 (1H, m), 5.92
(1H, d, J ¼ 7:3 Hz), 5.93 (1H, d, J ¼ 7:3 Hz), 6.67 (1H, d, J ¼ 7:9 Hz),
6.71 (1H, dd, J ¼ 7:9, 1.4 Hz), 6.82 (1H, d, J ¼ 1:4 Hz), 7.33–7.43
(6H, m), 7.62–7.67 (4H, m). NMR ꢁC (CDCl3): 4.8, 6.8, 19.3, 27.0,
30.4, 49.0, 63.0, 73.5, 100.7, 107.3, 107.4, 115.6, 120.2, 127.6, 129.5,
133.9, 135.6, 136.9, 137.3, 146.4, 147.2. Found: C, 71.60; H, 8.43.
silica gel column chromatography (1% EtOAc in toluene) gave threo-
20
22 (2.20 g, 2.91 mmol, 62%) as a colorless oil, ½ꢀꢂ
þ63 (c 0.8,
D
CHCl3). NMR ꢁH (CDCl3): 0.47 (6H, q, J ¼ 7:9 Hz), 0.81 (9H, t,
J ¼ 7:9 Hz), 1.00 (9H, s), 2.79 (1H, m), 3.04 (1H, dd, J ¼ 5:1, 4.0 Hz),

1614
T. NAKATO et al.
3.24 (1H, dd, J ¼ 10:6, 6.2 Hz), 3.67 (1H, dd, J ¼ 10:6, 4.0 Hz), 3.84
(3H, s), 3.88 (3H, s), 4.82 (1H, d, J ¼ 7:5 Hz), 5.29 (1H, d,
J ¼ 4:0 Hz), 5.93 (1H, d, J ¼ 3:9 Hz), 5.94 (1H, d, J ¼ 3:9 Hz), 6.60
(1H, d, J ¼ 9:5 Hz), 6.70 (1H, s), 6.71 (1H, d, J ¼ 8:3 Hz), 6.80 (1H, d,
J ¼ 8:3 Hz), 6.88 (1H, dd, J ¼ 8:3, 1.8 Hz), 6.91 (1H, d, J ¼ 1:8 Hz),
7.28–7.33 (6H, m), 7.35–7.43 (2H, m), 7.47 (2H, d, J ¼ 7:9 Hz). NMR
ꢁC (CDCl3): 4.6, 6.7, 19.0, 26.8, 43.5, 52.7, 55.77, 55.84, 62.9, 72.8,
81.8, 101.1, 106.8, 108.0, 109.3, 110.7, 118.3, 119.3, 127.5, 127.6,
129.6, 129.7, 129.9, 132.8, 132.9, 133.1, 135.5, 135.6, 147.1, 147.6,
26.99, 43.6, 55.6, 55.9, 61.55, 61.59, 72.7, 73.1, 100.9, 106.4, 107.8,
108.6, 110.9, 117.6, 118.8, 127.7, 127.75, 127.79, 129.9, 129.98,
130.03, 132.08, 132.11, 132.2, 132.3, 135.55, 135.61, 136.3, 137.7,
146.3, 147.6, 147.7, 148.8. EIMS m=z: 882 (Mþ, 4), 448 (63), 432 (58),
199 (98), 135 (100). HRMS (EI) m=z (Mþ): calcd. for C53H62O8Si2,
20
882.3983; found, 882.3982. (1S,2S,3R,4R)-(24), ½ꢀꢂ
ꢀ9 (c 1.2,
D
CHCl3).
(7R,70R,8S,80R)-30,40-Dimethoxy-3,4-methylenedioxy-7,70-epoxy-
lignane-9,90-diol ((þ)-3). To an ice-cooled solution of 24 (0.54 g,
0.61 mmol) and Et3N (0.17 ml, 1.22 mmol) in CH2Cl2 (10 ml) was
added MsCl (0.66 ml, 0.83 mmol). The reaction mixture was stirred at
room temperature for 1 h before additions of sat. aq. NaHCO3 solution
and CH2Cl2. The organic solution was separated and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc=
148.6, 148.7, 176.0. Found: C, 68.62; H, 7.28. Calcd. for C43H54O8Si2:
20
C, 68.38; H, 7.21%. (2R,3R,4R)-[(S)]-(22). ½ꢀꢂ
ꢀ63 (c 0.8, CHCl3).
D
Determination of the stereochemistry as threo form. To an ice-cooled
solution of 22 (50 mg, 0.066 mmol) in THF (0.5 ml) was added 6 M aq.
HCl solution (0.5 ml). After the reaction solution was stirred at 0 ꢁC for
30 min, EtOAc was added. The organic solution was separated, washed
with sat. aq. NaHCO3 solution and brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc=
hexane ¼ 1=6) gave tetrahydrofuran compound as
a mixture of
(7R,70R) and (7S,70S) (0.34 g, 0.39 mmol, 64%). To a solution of this
mixture (0.34 g, 0.39 mmol) in THF (20 ml) was added TBAF (0.86 ml,
1 M in THF, 0.86 mmol). After the reaction solution was stirred at room
temperature for 1 h, sat aq. NH4Cl solution was added. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc=
hexane ¼ 1=3) and chiral column (OD-H, 1 ml/min, 280 nm, 20%
EtOH/hexane) gave desired (7R,70R,8S,80R)-(þ)-3, (tR 28 min, 62 mg,
hexane ¼ 1=3) gave a threo aldol product (37 mg, 0.058 mmol, 88%)
20
as a colorless oil, ½ꢀꢂ
ꢀ44 (c 0.7, CHCl3). NMR ꢁH (CDCl3): 0.97
D
(9H, s), 2.72 (1H, m), 2.94 (1H, dd, J ¼ 7:3, 7.3 Hz), 3.01 (2H, d,
J ¼ 6:2 Hz), 3.76 (3H, s), 3.77 (3H, s), 3.79 (1H, d, J ¼ 2:7 Hz, OH),
4.96 (1H, dd, J ¼ 7:3, 2.7 Hz, ArCHOH), 5.42 (1H, d, J ¼ 7:8 Hz),
5.94 (2H, s), 6.54 (1H, d, J ¼ 8:2 Hz), 6.64 (1H, dd, J ¼ 8:2, 1.5 Hz),
6.69–6.73 (3H, m), 6.82 (1H, d, J ¼ 1:5 Hz), 7.27–7.35 (6H, m), 7.37–
7.44 (4H, m). NMR ꢁC (CDCl3): 19.0, 26.8, 44.6, 49.6, 55.7, 55.8,
62.5, 73.7, 81.9, 101.2, 106.8, 108.1, 109.1, 110.8, 119.0, 127.6, 127.7,
129.1, 129.75, 129.82, 132.4, 132.5, 132.7, 135.5, 147.5, 147.7, 149.0,
149.2, 177.7. Found: C, 69.24; H, 6.33. Calcd. for C37H40O8Si: C,
69.35; H, 6.29%.
0.16 mmol, 41%) and undesired (7S,70S,8S,80R)-25 (tR 13 min, 85 mg,
20
0.22 mmol, 56%). (7R,70R,8S,80R)-(þ)-3, ½ꢀꢂ
þ76 (c 0.2, CHCl3).
D
NMR ꢁH (CDCl3): 2.04 (1H, br. s), 2.75 (2H, m), 3.07 (1H, br. s), 3.36
(1H, dd, J ¼ 10:0, 2.0 Hz), 3.68 (1H, dd, J ¼ 10:0, 9.6 Hz), 3.79–3.91
(2H, m), 3.88 (6H, s), 4.95 (1H, d, J ¼ 9:2 Hz), 5.48 (1H, d, J ¼ 5:0
Hz), 5.96 (2H, s), 6.78 (1H, d, J ¼ 7:9 Hz), 6.83–7.00 (4H, m), 7.26
(1H, s). NMR ꢁC (CDCl3): 48.4, 54.4, 55.90. 55.94, 59.8, 81.1, 82.9,
101.0, 106.2, 108.2, 108.8, 111.1, 117.8, 119.4, 131.5, 136.6, 147.2,
148.0, 148.2, 149.0. EIMS m=z: 388 (Mþ, 100), 191 (73), 174 (75).
(1S,2S,3R,4R)-2,3-Bis[(tert-butyldiphenylsilyloxy)methyl]-4-(3,4-
dimethoxyphenyl)-4-(triethylsilyloxy)-1-(3,4-methylenedioxyphenyl)-1-
butanol (23). To an ice-cooled solution of LiBH4 (2.65 g, 0.12 mol) in
THF (40 ml) was added a solution of 22 (2.20 g, 2.91 mmol) in THF
(10 ml), and then the resulting solution was stirred at 65 ꢁC for 3 h
before addition of sat. aq. NH4Cl solution. After concentration of the
mixture, the residue was dissolved in EtOAc and H2O. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration gave a crude diol. A reaction solution of crude diol,
Et3N (0.44 ml, 3.16 mmol), DMAP (29 mg, 0.24 mmol), and TBDPSCl
(0.72 ml, 2.77 mmol) in CH2Cl2 (20 ml) was stirred at room temper-
ature for 2 h before additions of H2O and CH2Cl2. The organic solution
was separated, washed with brine, and dried (Na2SO4). Concentration
HRMS (EI) m=z (Mþ): calcd. for C21H24O7, 388.1522; found,
20
388.1521. (7S,70S,8R,80S)-(ꢀ)-(3), tR 16 min, ½ꢀꢂ
ꢀ76 (c 0.2,
D
CHCl3).
(7R,70R,8S,80R)-30,40,9,90-Tetramethoxy-3,4-methylenedioxy-7,70-
epoxylignane ((þ)-4). To an ice-cooled suspension of NaH (13 mg,
60% oil suspension, 0.34 mmol) in THF (3 ml) was added (þ)-3
(60 mg, 0.15 mmol) in THF (2 ml). After the mixture was stirred at
room temperature for 30 min, CH3I (0.47 ml, 7.55 mmol) was added.
The resulting reaction solution was stirred at room temperature for 16 h
before additions of sat. aq. NH4Cl solution and EtOAc. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc=
followed by silica gel column chromatography (EtOAc/hexane ¼ 1=7)
20
gave 23 (1.79 g, 1.79 mmol, 62%, 2 steps) as a colorless oil, ½ꢀꢂ
D
þ43 (c 0.9, CHCl3). NMR ꢁH (CDCl3): 0.18–0.24 (6H, m), 0.63 (9H, t,
J ¼ 7:9 Hz), 1.00 (9H, s), 1.03 (9H, s), 2.09 (1H, m), 2.43 (1H, m),
3.62 (3H, s), 3.83 (3H, s), 3.83–3.88 (2H, m), 4.00 (2H, d, J ¼ 6:3 Hz),
4.65 (1H, d, J ¼ 5:4 Hz), 4.92 (1H, dd, J ¼ 4:0, 1.3 Hz), 5.10 (1H, d,
J ¼ 1:3 Hz), 5.90 (1H, d, J ¼ 6:3 Hz), 5.91 (1H, d, J ¼ 6:3 Hz), 6.45
(1H, s), 6.55 (1H, d, J ¼ 8:2 Hz), 6.59 (1H, d, J ¼ 8:2 Hz), 6.65–6.70
(2H, m), 6.80 (1H, s), 7.21–7.42 (12H, m), 7.46 (2H, d, J ¼ 6:8 Hz),
7.54–7.61 (6H, m). NMR ꢁC (CDCl3): 4.7, 6.7, 19.0, 19.1, 26.7, 26.9,
46.5, 48.2, 55.4, 55.7, 62.0, 64.6, 73.8, 77.2, 100.7, 107.3, 107.6, 109.4,
110.3, 118.8, 120.0, 127.4, 127.6, 129.5, 129.6, 132.7, 132.9, 133.0,
133.2, 135.4, 135.5, 135.6, 135.9, 137.5, 146.4, 147.5, 147.9, 148.3.
hexane ¼ 1=3) gave (þ)-4 (58 mg, 0.14 mmol, 93%) as a colorless oil,
20
½ꢀꢂ
þ45 (c 0.4, CHCl3). NMR ꢁH (CDCl3): 2.66 (1H, m), 2.71 (1H,
D
m), 3.08 (1H, dd, J ¼ 9:8, 3.3 Hz), 3.11 (3H, s), 3.20 (1H, dd, J ¼ 9:8,
3.9 Hz), 3.30 (3H, s), 3.45 (1H, dd, J ¼ 9:1, 5.7 Hz), 3.62 (1H, dd,
J ¼ 9:1, 8.4 Hz), 3.89 (6H, s), 4.97 (1H, d, J ¼ 8:2 Hz), 5.44 (1H, d,
J ¼ 5:7 Hz), 5.94 (2H, s), 6.77 (1H, d, J ¼ 8:1 Hz), 6.83–6.89 (3H, m),
6.93 (1H, s), 7.03 (1H, s). NMR ꢁC (CDCl3): 46.3, 51.7, 55.8, 55.9,
58.5, 58.8, 69.2, 70.4, 82.7, 83.5, 100.9, 106.5, 108.0, 109.6, 110.6,
118.5, 119.4, 132.2, 137.6, 146.9, 147.8, 148.0, 148.6. EIMS m=z: 416
(Mþ, 72), 208 (86), 173 (100). HRMS (EI) m=z (Mþ): calcd. for
Found: C, 70.95; H, 7.75. Calcd. for C59H76O8Si3: C, 71.03; H, 7.68%.
20
C
23H28O7, 416.1835; found, 416.1837. >99% ee (HPLC, DAICEL
OD-H chiral column, detected at 280 nm, 1 ml minꢀ1, 10% EtOH in
(1R,2R,3S,4S)-(23), ½ꢀꢂ
ꢀ43 (c 1.3, CHCl3).
D
20
hexane, tR 26 min). (7S,70S,8R,80S)-(ꢀ)-4, ½ꢀꢂ
ꢀ45 (c 0.1, CHCl3),
D
>99% ee, tR 11 min.
(1R,2R,3S,4S)-2,3-Bis[(tert-butyldiphenylsilyloxy)methyl]-1-(3,4-
dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-1,4-butanediol (24).
To an ice-cooled solution of 23 (0.63 g, 0.63 mmol) in THF (2 ml)
was added 6 M aq. HCl solution (2 ml). The resulting solution was
stirred at 0 ꢁC for 1 h before additions of sat. aq. NaHCO3 solution and
EtOAc. The organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel column chro-
(S)-4-Benzyl-3-{(S)-2-[(S)-(3,4-dimethoxyphenyl)(triethylsilyloxy)-
methyl]-4-pentenoyl}-2-oxazolidinone (27). To an ice-cooled solution
of 26 (8.33 g, 20.0 mmol) and 2,6-lutidine (4.51 ml, 38.7 mmol) in
CH2Cl2 (70 ml) was added TESOTf (6.53 ml, 28.9 mmol). After the
reaction solution was stirred at 0 ꢁC for 30 min, sat. aq. NaHCO3
solution was added. The organic solution was separated, washed with
sat. aq. CuSO4 solution and sat. aq. NaHCO3 solution, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
matography (EtOAc/hexane ¼ 1=3) gave 24 (0.51 g, 0.58 mmol, 92%)
20
as a colorless oil, ½ꢀꢂ
þ9 (c 1.7, CHCl3). NMR ꢁH (CDCl3): 1.06
D
(9H, s), 1.07 (9H, s), 2.40 (2H, m), 3.75 (3H, s), 3.82–3.91 (4H, m),
3.90 (3H, s), 3.95 (2H, br. s), 4.77 (1H, br. d, J ¼ 5:3 Hz), 4.84 (1H, br.
d, J ¼ 6:5 Hz), 5.95 (2H, s), 6.67 (1H, d, J ¼ 7:9 Hz), 6.71 (2H, d,
J ¼ 8:0 Hz), 6.77 (1H, s), 6.80 (2H, s), 7.24–7.42 (8H, m), 7.33–7.42
(4H, m), 7.48–7.56 (8H, m). NMR ꢁC (CDCl3): 19.05, 19.10, 26.96,
raphy (EtOAc/hexane ¼ 1=5) gave 27 (10.4 g, 19.3 mmol, 97%) as a
20
colorless oil, ½ꢀꢂ
ꢀ79 (c 1.1, CHCl3). NMR ꢁH (CDCl3): 0.41–0.56
D
(6H, m), 0.87 (9H, t, J ¼ 7:8 Hz), 2.60 (1H, dd, J ¼ 13:3, 9.8 Hz), 2.66
(1H, m), 2.74 (1H, m), 3.11 (1H, dd, J ¼ 13:3, 3.2 Hz), 3.52 (1H, dd,

Tetrasubstituted Tetrahydrofuran Lignan
1615
J ¼ 8:7, 8.3 Hz), 3.83 (3H, s), 3.87 (3H, s), 3.89 (1H, dd, J ¼ 8:7,
1.7 Hz), 4.15 (1H, m), 4.49 (1H, m), 4.70 (1H, d, J ¼ 8:3 Hz), 5.02
(1H, d, J ¼ 10:3 Hz), 5.12 (1H, d, J ¼ 17:1 Hz), 5.87 (1H, m), 6.12
(1H, d, J ¼ 7:8 Hz), 6.78 (1H, d, J ¼ 8:3 Hz), 6.98 (1H, s), 7.13–7.15
(2H, m), 7.21–7.31 (3H, m). NMR ꢁC (CDCl3): 4.7, 6.7, 33.9, 37.9,
51.4, 55.7, 55.78, 55.81, 65.6, 76.5, 109.7, 110.0, 116.7, 119.0, 127.2,
128.8, 129.4, 135.2, 135.3, 135.6, 148.4, 148.6, 152.8, 173.7. Found:
dissolved in H2O and EtOAc. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration gave a crude
triol. A reaction solution of this crude triol, Et3N (1.57 ml, 11.3 mmol),
DMAP (49 mg, 0.40 mmol), and TBDPSCl (2.42 ml, 9.31 mmol) in
CH2Cl2 (5 ml) was stirred at room temperature for 3 h before additions
of H2O and CH2Cl2. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed by silica
gel column chromatography (EtOAc/hexane ¼ 1=9 and 1/4) gave
(1S,2R,3R,4S)-isomer 30 (3.21 g, 3.21 mmol, 67%, 2 steps) as a
C, 66.98; H, 7.70; N 2.63. Calcd. for C30H41O6NSi: C, 66.76; H, 7.66;
20
N, 2.60%. (R)-{(R)-[(R)]}-(27), ½ꢀꢂ
þ81 (c 1.8, CHCl3).
D
colorless oil and (1R,2R,3R,4S)-isomer 31 (0.69 g, 0.69 mmol, 15%, 2
20
steps) as a colorless oil. (1S,2R,3R,4S) isomer 30, ½ꢀꢂ
ꢀ40 (c 1.2,
D
(R)-2-[(S)-(3,4-Dimethoxyphenyl)(triethylsilyloxy)methyl]-4-penten-
1-ol (28). To an ice-cooled solution of LiBH4 (1.68 g, 77.1 mmol) and
MeOH (1.59 ml) in THF (50 ml) was added 27 (10.4 g, 19.3 mmol) in
THF (50 ml), and then the reaction solution was stirred at room
temperature for 30 min before addition of sat. aq. NH4Cl solution.
After concentration, the residue was dissolved in EtOAc and H2O.
The organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
CHCl3). NMR ꢁH (CDCl3): 0.21–0.27 (6H, m), 0.65 (9H, t,
J ¼ 8:1 Hz), 1.02 (9H, s), 1.07 (9H, s), 2.01 (1H, m), 2.36 (1H, m),
3.59 (1H, dd, J ¼ 10:3, 6.3 Hz), 3.62–3.66 (1H, overlapped), 3.64 (3H,
s), 3.84 (3H, s), 3.88 (1H, dd, J ¼ 9:3, 4.4 Hz), 4.04 (1H, dd, J ¼ 9:3,
8.8 Hz), 4.31 (1H, d, J ¼ 5:9 Hz), 4.62 (1H, d, J ¼ 3:9 Hz), 5.18 (1H,
br. s), 5.93 (1H, d, J ¼ 15:9 Hz), 5.94 (1H, d, J ¼ 15:9 Hz), 6.21 (1H,
s), 6.35 (1H, s), 6.49 (1H, d, J ¼ 8:3 Hz), 6.58–6.61 (3H, m), 7.25–7.30
(2H, m), 7.34–7.44 (10H, m), 7.56–7.65 (6H, m), 7.69–7.72 (2H, m).
NMR ꢁC (CDCl3): 4.5, 6.7, 19.0, 19.2, 26.8, 26.9, 44.5, 44.9, 55.2,
55.5, 63.5, 63.8, 72.3, 74.7, 100.8, 106.1, 107.1, 108.4, 109.9, 118.0,
118.4, 127.6, 127.69, 127.72, 129.5, 129.6, 129.7, 129.8, 132.5, 132.8,
133.3, 133.7, 135.5, 135.55, 135.64, 135.7, 138.2, 145.6, 147.1, 147.6,
raphy (EtOAc/hexane ¼ 1=4) gave 28 (2.90 g, 7.91 mmol, 41%) as a
20
colorless oil, ½ꢀꢂ
ꢀ39 (c 1.3, CHCl3). NMR ꢁH (CDCl3): 0.45–0.60
D
(6H, m), 0.89 (9H, t, J ¼ 8:1 Hz), 1.86 (1H, m), 2.00–2.13 (2H, m),
2.76 (1H, br. s), 3.47 (1H, dd, J ¼ 11:0, 3.7 Hz), 3.59 (1H, dd,
J ¼ 11:0, 7.6 Hz), 3.88 (3H, s), 3.89 (3H, s), 4.84 (1H, d, J ¼ 4:9 Hz),
5.02–5.06 (2H, m), 5.78 (1H, m), 6.80–6.85 (2H, m), 6.92 (1H, d,
J ¼ 1:5 Hz). NMR ꢁC (CDCl3): 4.6, 6.7, 31.8, 47.4, 55.7, 55.8, 63.0,
76.7, 109.9, 110.4, 116.3, 119.0, 134.5, 137.0, 148.2, 148.6. Found: C,
148.2. Found: C, 69.79; H, 7.55. Calcd. for C59H76O8Si3: C, 71.04; H,
20
7.68%. (1R,2S,3S,4R)-30, ½ꢀꢂ
þ39 (c 1.8, CHCl3). (1R,2R,3R,4S)
D
20
isomer 31, ½ꢀꢂ
ꢀ67 (c 1.1, CHCl3). NMR ꢁH (CDCl3): 0.21 (6H, q,
D
J ¼ 7:8 Hz), 0.60 (9H, t, J ¼ 7:8 Hz), 0.91 (9H, s), 0.94 (9H, s), 1.56
(1H, m), 2.26 (1H, m), 3.48 (1H, dd, J ¼ 10:3, 8.3 Hz), 3.54–3.58 (1H,
overlapped), 3.55 (3H, s), 3.77 (3H, s), 3.92 (1H, dd, J ¼ 9:8, 7.6 Hz),
4.08 (1H, dd, J ¼ 9:8, 4.4 Hz), 4.39 (1H, s), 4.50 (1H, d, J ¼ 8:8 Hz),
4.80 (1H, d, J ¼ 3:4 Hz), 5.81 (1H, d, J ¼ 20:0 Hz), 5.82 (1H, d,
J ¼ 20:0 Hz), 6.17–6.20 (3H, m), 6.42 (1H, d, J ¼ 7:8 Hz), 6.51 (1H,
d, J ¼ 7:8 Hz), 6.57 (1H, d, J ¼ 8:3 Hz), 7.23–7.30 (8H, m), 7.31–7.37
(4H, m), 7.45–7.49 (4H, m), 7.51–7.56 (4H, m). NMR ꢁC (CDCl3): 4.7,
6.8, 19.0, 19.1, 26.86, 26.93, 43.1, 48.8, 55.2, 55.7, 62.1, 65.3, 73.4,
77.8, 100.9, 106.8, 107.0, 108.5, 110.2, 113.6, 118.1, 120.9, 127.6,
127.70, 127.72, 129.6, 129.8, 132.76, 132.81, 133.2, 133.4, 135.57,
135.65, 135.70, 136.2, 137.0, 146.5, 147.5, 147.7, 148.4. Found: C,
65.81; H, 9.46. Calcd. for C20H34O4Si: C, 65.53; H, 9.35%. (S)-[(R)]-
20
28, ½ꢀꢂ
þ40 (c 1.5, CHCl3).
D
(R)-3-[(S)-(3,4-Dimethoxyphenyl)(triethylsilyloxy)methyl]-4-buta-
nolide (29). A reaction solution of 28 (2.70 g, 7.37 mmol), NMO
(1.15 g, 9.82 mmol), and OsO4 (1.5 ml, 2% aq. solution) in acetone
(60 ml), tert-BuOH (15 ml), and H2O (15 ml) was stirred at room
temperature for 16 h before addition of sat. aq. Na2S2O3 solution. After
concentration, the residue was dissolved in H2O and EtOAc. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration gave a crude glycol. A reaction mixture of
this crude glycol and NaIO4 (2.05 g, 9.58 mmol) in MeOH (150 ml)
was stirred at room temperature for 1 h before concentration. The
residue was dissolved in EtOAc and H2O. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentration gave
a crude hemiacetal. A reaction mixture of this hemiacetal, PCC (2.06 g,
9.56 mmol), and MS 4A (0.5 g) in CH2Cl2 (150 ml) was stirred at room
temperature for 16 h before addition of ether. After filtration, the
filtrate was concentrated, and then the residue was applied to silica gel
71.51; H, 7.74. Calcd. for
20
C
59H76O8Si3: C, 71.04; H, 7.68%.
(1S,2S,3S,4R)-isomer31, ½ꢀꢂ
þ65 (c 1.7, CHCl3).
D
(1S,2R,3R,4S)-2,3-Bis[(tert-butyldiphenylsilyloxy)methyl]-1-(3,4-
dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-1,4-butanediol (32)
and (1S,2R,3R,4R)-2,3-bis[(tert-butyldiphenylsilyloxy)methyl]-1-(3,4-
dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-1,4-butanediol (33).
To an ice-cooled solution of (1S,2R,3R,4S)-30 (0.12 g, 0.12 mmol) in
THF (2 ml) was added 6 M aq. HCl solution (1 ml). After the reaction
solution was stirred at room temperature for 10 min, sat. aq. NaHCO3
solution and EtOAc were added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography (EtOAc/hexane ¼ 1=4) gave
column chromatography (EtOAc/hexane ¼ 1=4) to give 29 (1.91 g,
20
5.21 mmol, 71%, 3 steps) as a colorless oil, ½ꢀꢂ
ꢀ67 (c 1.0, CHCl3).
D
NMR ꢁH (CDCl3): 0.46–0.56 (6H, m), 0.87 (9H, t, J ¼ 8:1 Hz), 2.48
(1H, dd, J ¼ 17:8, 8.8 Hz), 2.65 (1H, dd, J ¼ 17:8, 6.8 Hz), 2.79 (1H,
m), 3.88 (6H, s), 4.07 (1H, dd, J ¼ 9:3, 6.1 Hz), 4.18 (1H, dd, J ¼ 9:3,
6.8 Hz), 4.58 (1H, d, J ¼ 5:9 Hz), 6.78 (1H, dd, J ¼ 8:3, 2.0 Hz), 6.82
(1H, d, J ¼ 8:3 Hz), 6.84 (1H, d, J ¼ 1:5 Hz). NMR ꢁC (CDCl3): 4.7,
6.7, 30.4, 44.2, 55.8, 70.1, 75.1, 108.9, 110.8, 118.3, 134.8, 148.7,
(1S,2R,3R,4S)-32 (77 mg, 0.087 mmol, 73%) as colorless crystals, mp
20
166–168 ꢁC (20% EtOAc in hexane), ½ꢀꢂ
þ28 (c 1, CHCl3). NMR
D
149.1, 177.0. Found: C, 62.17; H, 8.11. Calcd. for C19H30O5Si: C,
20
ꢁH (CDCl3): 1.06 (9H, s), 1.08 (9H, s), 2.31 (1H, m), 2.36 (1H, m),
3.67 (3H, s), 3.84 (1H, dd, J ¼ 10:9, 4.9 Hz), 3.87 (3H, s), 4.00 (1H,
dd, J ¼ 10:9, 2.9 Hz), 4.05 (2H, d, J ¼ 6:7 Hz), 4.60–4.68 (2H, m),
5.93 (1H, d, J ¼ 20:5 Hz), 5.94 (1H, d, J ¼ 20:5 Hz), 6.20 (1H, s), 6.34
(1H, s), 6.46 (1H, d, J ¼ 8:0 Hz), 6.54–6.55 (2H, m), 6.67 (1H, d,
J ¼ 8:3 Hz), 7.35–7.41 (8H, m), 7.43–7.47 (4H, m), 7.65–7.67 (8H,
m). NMR ꢁC (CDCl3): 19.0, 19.1, 26.8, 44.95, 45.03, 55.2, 55.7, 64.6,
64.8, 73.7, 73.8, 101.0, 106.0, 107.3, 108.4, 110.4, 117.7, 118.6, 127.8,
127.9, 129.95, 130.01, 132.35, 132.38, 132.5, 135.50, 135.54, 135.59,
135.63, 135.8, 137.3, 146.1, 147.3, 147.6, 148.5. EIMS m=z: 882 (Mþ,
62.26; H, 8.25%. (S)-[(R)]-(29), ½ꢀꢂ
þ68 (c 1.0, CHCl3).
D
(1S,2R,3R,4S)-2,3-Bis[(tert-butyldiphenylsilyloxy)methyl]-4-(3,4-
dimethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-4-(triethylsilyloxy)-1-
butanol (30) and (1R,2R,3R,4S)-2,3-bis[(tert-butyldiphenylsilyloxy)-
methyl]-4-(3,4-dimethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-4-(tri-
ethylsilyloxy)-1-butanol (31). To a solution of KHMDS (12.2 ml, 0.5 M
in toluene, 6.10 mmol) in THF (10 ml) was added a solution of 29
(1.91 g, 5.21 mmol) in THF (5 ml) and a solution of piperonal (0.87 g,
5.79 mmol) in THF (5 ml) at ꢀ70 ꢁC. The resulting reaction solution
was stirred at ꢀ70 ꢁC for 1 h before additions of sat. aq. NH4Cl
solution and EtOAc. The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration followed by silica gel
column chromatography (EtOAc/hexane ¼ 1=3) gave a 5/1 mixture of
an erythro/threo-aldol product (2.45 g, 4.74 mmol, 91%). To a solution
of LiBH4 (0.80 g, 36.7 mmol) in THF (20 ml) was added a solution
of this aldol mixture (2.45 g, 4.74 mmol) in THF (40 ml) at 0 ꢁC. After
the reaction mixture was stirred at 0 ꢁC for 16 h, sat. aq. NH4Cl
solution was added. After concentration of the mixture, the residue was
4), 551 (50), 199 (100). HRMS (EI) m=z (Mþ): calcd. for C53H62O8Si2,
20
882.3983; found, 882.3985. (1R,2S,3S,4R)-32, ½ꢀꢂ
ꢀ28 (c 0.6,
D
CHCl3). (1S,2R,3R,4R)-isomer 33. Diol 33 was obtained from 31 in
20
78% yield as a colorless oil, ½ꢀꢂ
ꢀ18 (c 1.1, CHCl3). NMR ꢁH
D
(CDCl3): 1.02 (9H, s), 1.03 (9H, s), 2.21 (1H, m), 2.31 (1H, m), 3.71
(3H, s), 3.82–3.92 (4H, m), 3.90 (3H, s), 3.94 (1H, br. s), 4.05 (1H, br.
s), 4.49 (1H, d, J ¼ 5:4 Hz), 4.83 (1H, br. s), 5.89 (2H, s), 6.33–6.35
(2H, m), 6.54 (1H, d, J ¼ 8:3 Hz), 6.67 (1H, s), 6.72 (1H, d,
J ¼ 8:1 Hz), 6.80 (1H, d, J ¼ 8:2 Hz), 7.25–7.49 (14H, m), 7.59–7.64
(6H, m). NMR ꢁC (CDCl3): 18.96, 19.0, 26.7, 26.8, 45.3, 49.8, 55.5,

1616
T. NAKATO et al.
56.0, 62.2, 63.8, 73.2, 77.2, 100.8, 106.5, 107.4, 108.8, 110.9, 117.8,
119.5, 127.7, 127.8, 129.8, 129.91, 129.93, 132.16, 132.22, 132.6,
132.7, 135.32, 135.53, 135.6, 136.3, 136.8, 146.4, 147.4, 147.8, 148.8.
EIMS m=z: 882 (Mþ, 1), 551 (50), 199 (100), 135 (71). HRMS (EI)
m=z (Mþ): calcd. for C53H62O8Si2, 882.3983; found, 882.3980.
55.86, 55.89, 59.00, 72.26, 72.33, 82.76, 82.82, 100.89, 106.7, 108.0,
109.4, 110.9, 118.5, 119.6, 134.9, 136.6, 146.8, 147.8, 148.4, 149.0.
EIMS m=z: 416 (Mþ, 100), 208 (93). HRMS (EI) m=z (Mþ): calcd. for
C
23H28O7, 416.1835; found, 416.1835. >99% ee (HPLC, DAICEL
OD-H chiral column, detected at 280 nm, 1 ml minꢀ1, 5% EtOH in
20
hexane, tR 13 min). (7R,70R,8S,80S)-(þ)-6, ½ꢀꢂ
þ27 (c 0.8, CHCl3),
D
(7S,70S,8R,80R)-9,90-Bis[(tert-butyldiphenylsilyloxy)methyl]-30,40-
dimethoxy-3,4-methylenedioxy-7,70-epoxylignane (34). Method A. A
reaction solution of (1S,2R,3R,4S)-32 (49 mg, 0.055 mmol) and CSA
(5 mg, 0.022 mmol) in CH2Cl2 (10 ml) was stirred at room temperature
for 18 h before addition of a few drops of Et3N. After concentration of
the mixture, the residue was applied to silica gel column chromatog-
raphy (EtOAc/hexane ¼ 1=6) to give 34 (46 mg, 0.053 mmol, 96%) as
a colorless oil. Method B. To an ice-cooled solution of (1S,2R,3R,4S)-
30 (1.06 g, 1.06 mmol) and Et3N (0.16 ml, 1.15 mmol) in benzene
(10 ml) was added MsCl (0.089 ml, 1.15 mmol). After the reaction
mixture was stirred at 0 ꢁC for 1 h, ether and H2O were added. The
organic solution was separated, washed with brine, and dried
(Na2SO4). After concentration, the residue was dissolved in THF
(10 ml). To this solution was added n-Bu4NF (1.17 ml, 1 M in THF,
1.17 mmol) at ꢀ10 ꢁC. After the reaction solution was stirred at
ꢀ10 ꢁC for 1 h, sat. aq. NH4Cl solution and EtOAc were added. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
>99% ee (HPLC, DAICEL OD-H chiral column, detected at 280 nm,
1 ml minꢀ1, 5% EtOH in hexane, tR 15 min).
(2S,5S)-2-(3,4-Dimethoxyphenyl)-5-(3,4-methylenedioxyphenyl) tet-
rahydrofuran-3,4-diylidene (35). To an ice-cooled solution of
(7S,70S,8S,80R)-25 (0.25 g, 0.64 mmol) and Et3N (0.36 ml, 2.58 mmol)
in CH2Cl2 (10 ml) was added MsCl (0.19 ml, 2.45 mmol). After the
resulting reaction mixture was stirred at room temperature for 30 min,
H2O and CH2Cl2 were added. The organic solution was separated and
dried (Na2SO4). After concentration, a reaction mixture of the residue,
NaI (0.29 g, 1.93 mmol), and DBU (0.19 ml, 1.27 mmol) in DMF (8 ml)
was stirred at 80 ꢁC for 3 h before additions of H2O and EtOAc. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column chromatog-
raphy (EtOAc/hexane ¼ 1=3) gave unstable 35 (0.13 g, 0.37 mmol,
58%) as a colorless oil. NMR ꢁH (CDCl3): 3.88 (3H, s), 3.89 (3H, s),
4.89 (2H, s), 5.53 (1H, s), 5.57 (1H, s), 5.62 (2H, s), 5.95 (2H, s), 6.78
(1H, d, J ¼ 7:8 Hz), 7.83–6.89 (3H, m), 6.92–6.94 (2H, m). NMR ꢁC
(CDCl3): 55.9, 82.7, 82.8, 101.0, 106.0, 106.1, 106.2, 107.6, 108.0,
110.3, 110.8, 119.7, 120.9, 133.5, 135.2, 147.3, 147.7, 147.8, 148.9,
149.1. EIMS m=z: 352 (Mþ, 47), 219 (100). HRMS (EI) m=z (Mþ):
calcd. for C21H20O5, 352.1311; found, 352.1310. From diol (ꢀ)-5, 35
was obtained in 52% yield.
raphy (EtOAc/hexane ¼ 1=9) gave 34 (0.17 g, 0.20 mmol, 19%). From
20
(1R,2R,3R,4S)-31, 34 was obtained in 15% yield. ½ꢀꢂ
ꢀ25 (c 1.0,
D
CHCl3). NMR ꢁH (CDCl3): 1.011 (9H, s), 1.014 (9H, s), 2.44 (2H, m),
3.60–3.67 (4H, m), 3.80 (3H, s), 3.87 (3H, s), 5.15 (1H, d, J ¼ 7:8 Hz),
5.18 (1H, d, J ¼ 7:8 Hz), 5.93 (2H, s), 6.71 (2H, s), 6.77 (1H, d,
J ¼ 8:3Hz), 6.83 (1H, dd, J ¼ 8:3, 1.5 Hz), 6.88 (1H, s), 6.94 (1H, d,
J ¼ 1:5 Hz), 7.25–7.41 (16H, m), 7.52–7.60 (4H, m). NMR ꢁC
(CDCl3): 19.27, 19.31, 26.9, 51.8, 52.1, 55.7, 55.9, 61.3, 61.5, 82.3,
82.4, 100.9, 106.7, 107.9, 109.2, 110.9, 118.7, 119.7, 127.67, 127.69,
127.7, 129.68, 129.71, 129.8, 133.2, 133.4, 135.2, 135.5, 135.58,
135.61, 136.9, 146.8, 147.8, 148.4, 149.1. EIMS m=z: 864 (Mþ, 29),
551 (56), 253 (68), 197 (56), 135 (100). HRMS (EI) m=z (Mþ): calcd.
(7S,70S,8S,80S)-30,40-Dimethoxy-3,4-methylenedioxylignane-9,90-diol
((ꢀ)-7). To an ice-cooled solution of 35 (0.15 g, 0.43 mmol) in THF
.
(10 ml) was added BH3 SMe2 (0.20 ml, 2.11 mmol). The reaction
solution was stirred at room temperature for 1 h, and then H2O2 and
sat. aq. NaHCO3 solution were added. After the mixture was stirred at
room temperature for 2 h, CHCl3 was added. The organic solution was
separated and dried (Na2SO4). Concentration followed by silica gel
for
½ꢀꢂ
C
53H60O7Si2, 864.3877; found, 864.3878. (7R,70R,8S,80S)-34,
20
þ25 (c 0.8, CHCl3).
column chromatography (EtOAc/hexane ¼ 3=2) gave (ꢀ)-7 (78 mg,
D
20
0.20 mmol, 47%) as a colorless oil, ½ꢀꢂ
ꢀ22 (c 0.2, CHCl3). NMR
D
(7S,70S,8R,80R)-30,40-Dimethoxy-3,4-methylenedioxy-7,70-epoxy-
ꢁH (CDCl3): 2.02 (1H, br. s), 2.29 (1H, br. s), 2.73 (2H, m), 3.13–3.20
(2H, m), 3.56 (2H, dd, J ¼ 11:3, 2.3 Hz), 3.89 (3H, s), 3.91 (3H, s),
5.52 (1H, d, J ¼ 6:2 Hz), 5.54 (1H, d, J ¼ 6:9 Hz), 5.97 (2H, s), 6.79
(2H, s), 6.84–6.87 (4H, m). NMR ꢁC (CDCl3): 49.0, 49.1, 56.0, 62.71,
62.74, 82.55, 82.62, 101.1, 106.7, 108.1, 109.4, 111.0, 118.3, 119.3,
132.9, 134.4, 147.0, 147.8, 148.9. EIMS m=z: 388 (Mþ, 55), 194 (100).
lignane-9,90-diol ((ꢀ)-5). A reaction solution of 34 (99 mg, 0.11 mmol)
and TBAF (0.25 ml, 1 M in THF, 0.25 mmol) in THF (5 ml) was stirred
at room temperature for 2 h before additions of sat. aq. NH4Cl solution
and EtOAc. The organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration followed by silica gel column
HRMS (EI) m=z (Mþ): calcd. for C21H24O7, 388.1522; found,
chromatography (EtOAc/hexane ¼ 2=1) gave (ꢀ)-5 (37 mg, 0.095
20
388.1524. (7R,70R,8R,80R)-(þ)-7, ½ꢀꢂ
þ22 (c 0.1, CHCl3)
20
D
mmol, 86%) as a colorless oil, ½ꢀꢂ
ꢀ54 (c 0.7, CHCl3). NMR ꢁH
D
(CDCl3): 2.25 (2H, m), 3.55 (2H, br. dd, J ¼ 10:1, 7.9 Hz), 3.73 (2H,
br. d, J ¼ 10:1 Hz), 3.77–3.89 (2H, br.), 3.86 (3H, s), 3.89 (3H, s), 4.70
(1H, d, J ¼ 8:3 Hz), 4.72 (1H, d, J ¼ 7:1 Hz), 5.95 (2H, s), 6.78 (2H,
s), 6.85 (2H, d, J ¼ 7:9 Hz), 6.91 (2H, d, J ¼ 6:2 Hz). NMR ꢁC
(CDCl3): 55.92, 56.86, 57.2, 62.7, 62.8, 83.1, 83.2, 101.1, 106.6, 108.1,
109.4, 111.0, 118.8, 119.8, 133.8, 135.6, 147.3, 148.0, 148.8, 149.2.
EIMS m=z: 388 (Mþ, 100), 194 (61), 174 (55). HRMS (EI) m=z (Mþ):
(7S,70S,8S,80S)-30,40,9,90-Tetramethoxy-3,4-methylenedioxy-7,70-epo-
xylignane ((ꢀ)-8). To an ice-cooled suspension of NaH (30 mg, 60% in
oil, 0.75 mmol) in THF (5 ml) was added a solution of (þ)-7 (30 mg,
0.077 mmol) in THF (10 ml). After the mixture was stirred at room
temperature for 30 min, CH3I (0.20 ml, 3.21 mmol) was added. The
reaction solution was stirred at room temperature for 16 h, and then sat.
aq. NH4Cl solution and EtOAc were added. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentration
calcd. for C21H24O7, 388.1522; found, 388.1521. (7R,70R,8S,80S)-
20
(þ)-5, ½ꢀꢂ
þ54 (c 1.1, CHCl3).
D
followed by silica gel column chromatography (EtOAc/hexane ¼ 1=2)
20
(7S,70S,8R,80R)-30,40,9,90-Tetramethoxy-3,4-methylenedioxy-7,70-
epoxylignane ((ꢀ)-6). To an ice-cooled suspension of NaH (9 mg, 60%
in oil, 0.23 mmol) in THF (5 ml) was added a solution of (ꢀ)-5 (40 mg,
0.10 mmol) in THF (2 ml). After the mixture was stirred at room
temperature for 30 min, CH3I (0.32 ml, 5.14 mmol) was added, and
then the reaction solution was stirred at room temperature for 16 h
before additions of sat. aq. NH4Cl solution and EtOAc. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc=
gave (ꢀ)-8 (32 mg, 0.077 mmol, 100%) as a colorless oil, ½ꢀꢂ
ꢀ23
D
(c 0.3, CHCl3). NMR ꢁH (CDCl3): 2.74 (2H, m), 2.81–2.87 (2H, m),
3.14–3.18 (2H, overlapped), 3.16 (3H, s), 3.18 (3H, s), 3.89 (3H, s),
3.90 (3H, s), 5.53 (1H, d, J ¼ 4:8 Hz), 5.54 (1H, d, J ¼ 6:2 Hz), 5.96
(2H, s), 6.78–6.81 (2H, m), 6.84–6.90 (4H, m). NMR ꢁC (CDCl3):
45.3, 45.4, 55.85, 55.89, 58.7, 71.8, 82.29, 82.31, 100.9, 107.0, 107.9,
109.6, 110.7, 118.5, 119.5, 132.8, 134.3, 145.6, 147.5, 148.1, 148.6.
EIMS m=z: 416 (Mþ, 15), 208 (100). HRMS (EI) m=z (Mþ): calcd. for
C
23H28O7, 416.1835; found, 416.1836. >99% ee (HPLC, DAICEL
OD-H chiral column, detected at 280 nm, 1 ml minꢀ1, 5% EtOH in
hexane ¼ 1=3) gave (ꢀ)-6 (38 mg, 0.091 mmol, 91%) as a colorless
20
hexane, tR 14 min). (7R,70R,8R,80R)-(þ)-8, ½ꢀꢂ
þ23 (c 0.2, CHCl3),
20
D
oil, ½ꢀꢂ
ꢀ27 (c 0.9, CHCl3). NMR ꢁH (CDCl3): 2.36 (2H, m), 3.33
D
>99% ee, tR 22 min.
(6H, s), 3.42–3.46 (2H, m), 3.48 (2H, dd, J ¼ 9:5, 5.1 Hz), 3.87 (3H,
s), 3.90 (3H, s), 4.95 (1H, d, J ¼ 7:8 Hz), 4.97 (1H, d, J ¼ 9:0 Hz),
5.94 (2H, s), 6.77 (1H, d, J ¼ 7:9 Hz), 6.84 (1H, d, J ¼ 8:3 Hz), 6.88
(1H, dd, J ¼ 8:3, 1.6 Hz), 6.94 (1H, dd, J ¼ 8:3, 1.9 Hz), 6.97 (1H, d,
J ¼ 1:6 Hz), 7.00 (1H, d, J ¼ 1:9 Hz). NMR ꢁC (CDCl3): 51.0, 51.3,
(2S,5R)-2-(3,4-Dimethoxyphenyl)-5-(3,4-methylenedioxyphenyl)-
tetrahydrofuran-3,4-diylidene (37). A reaction solution of 36 (0.19 g,
0.49 mmol) and TsCl (0.47 g, 2.47 mmol) in pyridine (3 ml) was stirred

Tetrasubstituted Tetrahydrofuran Lignan
1617
at room temperature for 1 h before additions of H2O and EtOAc. The
organic solution was separated, washed with 1 M aq. HCl solution, sat.
aq. NaHCO3 solution, and brine, and dried (Na2SO4). After concen-
tration, a reaction solution of the residue, NaI (0.22 g, 1.47 mmol), and
DBU (0.15 ml, 1.00 mmol) in DMF (10 ml) was stirred at 80 ꢁC for 3 h
before additions of H2O and EtOAc. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentration
Ohguchi. Each fungus was cultured on potato dextrose agar (PDA,
Sigma-Aldrich, Canada).
Antibiotic spectra. The ability of each compound to inhibit the
growth of a variety of Gram-positive and Gram-negative bacterial
strains was assessed by the paper disc method (Advantec Toyo, Japan,
6-mm thin paper disc), and the minimum inhibitory concentration
(MIC) was determined for those strains that showed sensitivity to the
tested compounds. The paper disc test used agar plates containing
‘‘Nissui’’ nutrient broth (Nissui Pharmaceutical Co.) A hundred
microliter of an exponential culture of each respective strain was
made into molten agar containing the nutrient broth. After the agar had
solidified, a paper disc containing 15 ml of 50 mM of the tested
compound was put on to the agar plate. The plate was incubated for
24 h at 30 ꢁC (L. denitrificans and P. fluorescens) or at 37 ꢁC
(B. subtilis, S. aureus, E. coli, S. choleraesuis and Y. intermedia),
and the diameter of any halo of inhibition around the paper disc was
measured. The MIC value was determined from a two-fold dilution
series for any strain that showed a halo of inhibition. The test was done
three times.
followed by silica gel column chromatography (EtOAc/hexane ¼ 1=4)
20
gave 37 (60 mg, 0.17 mmol, 34%, 2 steps) as a colorless oil, ½ꢀꢂ
þ4
D
(c 0.7, CHCl3). NMR ꢁH (CDCl3): 3.887 (3H, s), 3.889 (3H, s), 4.68
(2H, m), 5.35 (2H, m), 5.52 (1H, d, J ¼ 3:9 Hz), 5.53 (1H, d,
J ¼ 2:9 Hz), 5.96 (2H, s), 6.80 (1H, d, J ¼ 8:3 Hz), 6.86–6.93 (4H, m),
6.98 (1H, dd, J ¼ 8:3, 1.9 Hz). NMR ꢁC (CDCl3): 55.85, 55.91, 83.39,
83.52, 101.1, 105.8, 107.9, 108.1, 110.89, 110.92, 113.7, 120.6, 121.9,
133.0, 134.6, 147.6, 147.9, 148.9, 149.0, 149.05, 149.09. EIMS m=z:
352 (Mþ, 2), 154 (100), 136 (62). HRMS (EI) m=z (Mþ): calcd. for
20
C21H20O5, 352.1311; found, 352.1309. (2R,3S)-37, ½ꢀꢂ
CHCl3).
ꢀ4 (c 1.1,
D
(7R,70S,8R,80S)-30,40-Dimethoxy-3,4-methylenedioxy-7,70-epoxy-
lignane-9,90-diol ((þ)-9). To an ice-cooled solution of 37 (60 mg,
.
0.17 mmol) in THF (2 ml) was added BH3 SMe2 (0.08 ml, 0.84 mmol).
Antifungal assay. The paper disc method was adopted for the first
screening. Briefly, fungal mycelia were spotted on the center of the
PDA plate (’100 mm dishes) and incubated at 28 ꢁC until the colony
diameter became 4–5 cm. A disc paper soaked in dimethyl sulfoxide
containing a test chemical was placed at the edge of the colony.
Growth inhibition was observed after culturing at 28 ꢁC for 7–10 d. A
further inhibition test was performed with the active compounds. Each
compound was added to three aliquots each containing 3 ml of PDA at
50 ꢁC, mixed rapidly and poured on to the PDA plates (’50 mm
dishes). Dimethyl sulfoxide without any test compound served as the
control. After incubating at 28 ꢁC for 7–10 d, the area of the mycelial
colony was measured by a caliper, the assays being triplicated.
The reaction solution was stirred at room temperature for 30 min. After
additions of sat. aq. NaHCO3 solution (4 ml) and 30% aq. H2O2
solution (4 ml), the resulting mixture was stirred at room temperature
for 2 h, and then EtOAc was added. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/hexane ¼ 1=3)
20
gave (þ)-9 (32 mg, 0.083 mmol, 49%) as a colorless oil, ½ꢀꢂ
þ3
D
(c 0.6, CHCl3). NMR ꢁH (CDCl3): 1.66 (1H, br. s), 2.66 (1H, br. s),
2.93 (2H, m), 3.39 (2H, dd, J ¼ 11:3, 3.7 Hz), 3.49 (2H, dd, J ¼ 11:3,
11.3 Hz), 3.89 (3H, s), 3.90 (3H, s), 5.12 (1H, d, J ¼ 5:1 Hz), 5.13 (1H,
d, J ¼ 6:5 Hz), 5.98 (2H, s), 6.81 (1H, d, J ¼ 8:1 Hz), 6.86–6.89 (3H,
m), 6.93 (1H, s), 6.97 (1H, d, J ¼ 8:1 Hz). NMR ꢁC (CDCl3): 48.0,
48.1, 55.92, 55.94, 60.88, 60.91, 80.95, 80.98, 101.1, 106.6, 108.2,
109.4, 111.2, 118.2, 119.3, 131.3, 132.8, 146.9, 147.8, 148.4, 148.9.
EIMS m=z: 388 (Mþ, 100), 222 (65), 191 (77), 174 (76). HRMS (EI)
Acknowledgments
m=z (Mþ): calcd. for C21H24O7, 388.1522; found, 388.1524.
We measured the 400 MHz NMR, MS and elemental
analysis data at INCS of Ehime University. Our thanks
to the president of Ehime University for supporting this
project. We are also grateful to Marutomo Co. for
financial support.
20
(7S,70R,8S,80R)-(ꢀ)-9, ½ꢀꢂ
ꢀ3 (c 0.7, CHCl3).
D
(7R,70S,8R,80S)-30,40,9,90-Tetramethoxy-3,4-methylenedioxy-7,70-epo-
xylignane ((þ)-10). To an ice-cooled suspension of NaH (16 mg, 60%
in oil, 0.39 mmol) was added (þ)-9 (14 mg, 0.036 mmol) in THF
(1 ml), and then the mixture was stirred at room temperature for
30 min. After addition of CH3I (0.11 ml, 1.77 mmol), the resulting
reaction solution was stirred at room temperature for 10 h, and then
H2O and EtOAc were added. The organic solution was separated,
washed with brine, and dried (Na2SO4). Concentration followed by
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10 (12 mg, 0.029 mmol, 81%) as a colorless oil, ½ꢀꢂ
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D
CHCl3). NMR ꢁH (CDCl3): 2.85 (2H, m), 3.01 (2H, dd, J ¼ 9:6,
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20
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D
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